Research Publications

Recommendations for real-world evidence of efficacy and safety of GLP-1 agonists in Prader-Willi syndrome: Report of a workshop held by FPWR and IPWSO

Prader-Willi syndrome (PWS) is a rare and complex genetic disorder characterised by physical, behavioural, and cognitive challenges. While infants with PWS often present with poor muscle tone, weak sucking ability, and feeding difficulties, older children and adults may struggle with hormone...

In-depth behavioral characterization of a rat model of Schaaf-Yang syndrome

Schaaf-Yang syndrome (SYS, OMIM #615547) is a rare neurodevelopmental disorder caused by truncating variants in the maternally imprinted MAGEL2 gene. It is characterized by intellectual disability, autism spectrum disorder, joint contractures, and feeding difficulties. Although MAGEL2 is deleted in ...

Comparing evidence-based telemental health treatments for caregivers of children with Prader Willi and Williams syndromes: feasibility, acceptability, and preliminary outcomes.

Caregivers of individuals with rare neurogenetic conditions often experience mental health challenges, often alongside substantial experiences of resilience. Unfortunately, caregiving burden can make accessing mental health support difficult, and restricted resources during the COVID-19 pandemic fur...

MAGEL2 (patho‐)physiology and Schaaf–Yang syndrome

Schaaf–Yang syndrome (SYS) is a complex neurodevelopmental disorder characterized by autism spectrum disorder, joint contractures, and profound hypothalamic dysfunction. SYS is caused by variants in MAGEL2, a gene within the Prader–Willi syndrome (PWS) locus on chromosome 15. In this review, we cons...

Inpatient Hospitalizations for COVID-19 Among Patients With Prader-Willi Syndrome: A National Inpatient Sample Analysis

Prader-Willi syndrome (PWS) is a genetic disorder associated with baseline respiratory impairment caused by multiple contributing etiologies. While this may be expected to increase the risk of severe COVID-19 infections in PWS patients, survey studies have suggested paradoxically low disease severit...

Inpatient hospitalisations for patients with Prader–Willi syndrome: a 2019–2021 National Inpatient Sample analysis

Background: Prader-Willi syndrome (PWS) is a genetic disorder characterised by hyperphagia, intellectual disability and increased propensity to a range of medical disorders. To better characterise the clinical presentation of PWS across the lifespan, this study reports on the demographics and clinic...

Circadian rhythm defects in Prader-Willi syndrome neurons

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by a spectrum of symptoms, including developmental delay, intellectual disability, and increased risk of autism. PWS is an imprinting disorder caused by the loss of paternal expression of critical genes in the 15q11.2-q13 reg...

High-throughput assessment of FMR1 and SNRPN methylation-based newborn screening using IsoPure and QIAcube HT systems

Aim This study compared methylation-specific quantitative melt analysis of FMR1 and SNRPN methylation (mDNA) using automated bisulfite conversion by the magnetic-bead-based IsoPure and column-based QIAcube HT systems. Methods Two bisulfite conversion methods were assessed on 3.2 mm punches from the ...

Altered Behavior and Neuronal Activity with Paternal Snord116 Deletion

Background/Objectives: Prader–Willi Syndrome (PWS) is a neurodevelopmental disease associated with multiple behavioral features, including a prevalence for psychosis. The genetic causes of PWS are well characterized and involve the silencing or deletion of the paternal copy of a region of chromosome...

snoRNA-facilitated protein secretion revealed by transcriptome-wide snoRNA target identification

Small nucleolar RNAs (snoRNAs) are non-coding RNAs known for guiding RNA modifications, including 2'-O-methylation (Nm) and pseudouridine (Ψ). While snoRNAs may also interact with other RNAs, such as mRNA, the full repertoire of RNAs targeted by snoRNA remains elusive due to the lack of effective te...

Validation of the Food Safe Zone questionnaire for families of individuals with Prader-Willi syndrome

Background Prader-Willi syndrome (PWS), a genetic neurodevelopmental disorder, is characterized by hyperphagia and significant behavioral problems. Hyperphagic individuals with PWS are chronically hungry yet rarely feel sated, and often engage in food-seeking behaviors. To avoid life-threatening obe...

Activation of the imprinted Prader-Willi syndrome locus by CRISPR-based epigenome editing

Background Epigenome editing with DNA-targeting technologies such as CRISPR-dCas9 can be used to dissect gene regulatory mechanisms and potentially treat associated disorders. For example, Prader-Willi syndrome (PWS) results from loss of paternally expressed imprinted genes on chromosome 15q11.2–q13...

Environmental enrichment normalizes metabolic function in the murine model of Prader-Willi syndrome Magel2-null mice

Prader-Willi syndrome (PWS) is a rare genetic disease that causes developmental delays, intellectual impairment, constant hunger, obesity, endocrine dysfunction, and various behavioral and neuropsychiatric abnormalities. Standard care of PWS is limited to strict supervision of food intake and growth...

Psychotic illness in people with Prader–Willi syndrome: a systematic review of clinical presentation, course and phenomenology

Background Prader–Willi syndrome (PWS) is a rare and complex neurodevelopmental disorder resulting from absent paternal expression of maternally imprinted genes at chromosomal locus 15q11-13. This absence of expression occurs as a consequence of a deletion on the chromosome 15 of paternal origin (ca...

Similar metabolic pathways are affected in both Congenital Myasthenic Syndrome-22 and Prader-Willi Syndrome

Loss of prolyl endopeptidase-like (PREPL) encoding a serine hydrolase with (thio)esterase activity leads to the recessive metabolic disorder Congenital Myasthenic Syndrome-22 (CMS22). It is characterized by severe neonatal hypotonia, feeding problems, growth retardation, and hyperphagia leading to r...

Roles of SNORD115 and SNORD116 ncRNA clusters during neuronal differentiation

In the snoRNA host gene SNHG14, 29 consecutive introns each generate SNORD116, and 48 tandem introns encode SNORD115. Loss of SNORD116 expression, but not of SNORD115, is linked to the neurodevelopmental disease Prader-Willi syndrome. SNORD116 and SNORD115 resemble box C/D small nucleolar RNAs (snoR...

Parallelized engineering of mutational models using piggyBac transposon delivery of CRISPR libraries

New technologies and large-cohort studies have enabled novel variant discovery and association at unprecedented scale, yet functional characterization of these variants remains paramount to deciphering disease mechanisms. Approaches that facilitate parallelized genome editing of cells of interest or...

Behavioral changes in patients with Prader-Willi syndrome receiving diazoxide choline extended-release tablets compared to the PATH for PWS natural history study

Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if ...

Newly developed oral bioavailable EHMT2 inhibitor as a potential epigenetic therapy for Prader-Willi syndrome

Prader-Willi syndrome (PWS) is the prototypic genomic disorder resulting from deficiency of paternally expressed genes in the human chromosome 15q11-q13 region. The unique molecular mechanism involving epigenetic modifications renders PWS as the most attractive candidate to explore a proof-of-concep...

AAV-BDNF gene therapy ameliorates a hypothalamic neuroinflammatory signature in the Magel2-null mouse model of Prader-Willi syndrome

Individuals with Prader-Willi syndrome (PWS) exhibit several metabolic and behavioral abnormalities associated with excessive food-seeking activity. PWS is thought to be driven in part by dysfunctional hypothalamic circuitry and blunted responses to peripheral signals of satiety. Previous work descr...

Caregiver-based perception of disease burden in Schaaf-Yang syndrome

Background: Schaaf-Yang syndrome (SYS) is a neurodevelopmental disorder caused by truncating variants in the paternally expressed MAGEL2 gene in the Prader-Willi syndrome-region on chromosome 15q. In addition to hypotonia and intellectual disability, individuals with SYS are frequently affected by n...

Analysis of SNHG14: A Long Non-Coding RNA Hosting SNORD116, Whose Loss Contributes to Prader–Willi Syndrome Etiology

The Small Nucleolar Host Gene 14 (SNHG14) is a host gene for small non-coding RNAs, including the SNORD116 small nucleolar C/D box RNA encoding locus. Large deletions of the SNHG14 locus, as well as microdeletions of the SNORD116 locus, lead to the neurodevelopmental genetic disorder Prader–Willi sy...

Examining Effective Intervention Strategies in a Play-Based Program for Children with Prader-Willi Syndrome

Background: Children with Prader-Willi Syndrome (PWS) display impaired pretend play abilities, reflective of broader social-cognitive challenges. Pretend play interventions for children with PWS demonstrate preliminary efficacy for improving cognitive and affective processes in play. It is unknown w...

Amygdala hyperactivation relates to eating behaviour: a potential indicator of food addiction in Prader–Willi syndrome.

Prader–Willi syndrome is a rare neurodevelopmental genetic disorder characterized by various endocrine, cognitive and behavioural problems. The symptoms include an obsession for food and reduced satiety, which leads to hyperphagia and morbid obesity. Neuropsychological studies have reported that Pra...

Effects of thermoneutrality on food intake, body weight, and body composition in a Prader-Willi syndrome mouse model

Objective: Prader-Willi syndrome (PWS) is a multisystem genetic disorder. Unfortunately, none of several mouse models carrying PWS mutations emulates the entirety of the human PWS phenotype, including hyperphagia plus obesity. Methods: To determine whether housing at thermoneutrality (TN, 30 °C) per...

The Feasibility and Effectiveness of a Novel, On-Line Social Skills Intervention for Individuals With Prader-Willi Syndrome

Introduction People with neurodevelopmental disabilities, including Prader-Willi syndrome (PWS), are at heightened risk for the negative sequalae of loneliness, including depression and anxiety. While societal factors such as stigma or limited social opportunities contribute to loneliness, so too do...

Insulin secretion deficits in a Prader-Willi syndrome β-cell model are associated with a concerted downregulation of multiple endoplasmic reticulum chaperones

Prader-Willi syndrome (PWS) is a multisystem disorder with neurobehavioral, metabolic, and hormonal phenotypes, caused by loss of expression of a paternally-expressed imprinted gene cluster. Prior evidence from a PWS mouse model identified abnormal pancreatic islet development with retention of aged...

Magel2 truncation alters select behavioral and physiological outcomes in a rat model of Schaaf-Yang syndrome

Previous studies in mice have utilized Magel2 gene deletion models to examine the consequences of its absence. We report the generation, molecular validation and phenotypic characterization of a novel rat model with a truncating Magel2 mutation modeling variants associated with Schaaf-Yang syndrome-...

Transcriptome-Wide Identification of 2′-O-Methylation Sites with RibOxi-Seq

The ability to detect 2′-O-methylation sites (Nm) in high-throughput fashion is important, as increasing evidence points to a more diverse landscape for this RNA modification as well as the possibility of yet unidentified functions. Here we describe an optimized version of RibOxi-seq, which is built...

Autonomic nervous system dysfunction in Prader–Willi syndrome

Introduction: Prader–Willi syndrome is a complex neurodevelopmental genetic disorder due to lack of paternal expression of critical imprinted genes in the 15q11.2-q13.1 chromosomal region, generally from a paternal deletion. Predominant features include infantile hypotonia, a poor suck with failure ...

Analysis of the hypothalamic oxytocin system and oxytocin receptor-expressing astrocytes in a mouse model of Prader–Willi syndrome

Prader–Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hyperphagia, obesity, developmental delay and intellectual disability. Studies suggest dysfunctional signaling of the neuropeptide oxytocin as one of the key mechanisms in PWS, and administration of oxytocin via intranasal...

Hypothalamic AAV-BDNF gene therapy improves metabolic function and behavior in the Magel2-null mouse model of Prader-Willi syndrome

Individuals with Prader-Willi syndrome (PWS) display developmental delays, cognitive impairment, excessive hunger, obesity, and various behavioral abnormalities. Current PWS treatments are limited to strict supervision of food intake and growth hormone therapy, highlighting the need for new therapeu...

The Prader-Willi Syndrome Anxiousness and Distress Behaviors Questionnaire: Development and Psychometric Validation

Objectives To facilitate the development of new therapies for Prader-Willi syndrome (PWS), we sought to develop a reliable and valid assessment of anxiousness and distress, common characteristics that have a significant negative impact on individuals with PWS and their families. Methods The PWS Anxi...

Non-coding RNAs associated with Prader-Willi syndrome regulate transcription of neurodevelopmental genes in human induced pluripotent stem cells

Mutations and aberrant gene expression during cellular differentiation lead to neurodevelopmental disorders, such as Prader-Willi syndrome (PWS) which results from the deletion of an imprinted locus on paternally inherited chromosome 15. We analysed chromatin-associated RNA in human induced pluripot...

Magel2 knockdown in hypothalamic POMC neurons innervating the medial amygdala reduces susceptibility to diet-induced obesity

Hyperphagia and obesity profoundly affect the health of children with Prader–Willi syndrome (PWS). The Magel2 gene among the genes in the Prader–Willi syndrome deletion region is expressed in proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC). Knockout of the Magel2 ...

Neurobehavioral Dimensions of Prader Willi Syndrome: Relationships Between Sleep and Psychosis-Risk Symptoms

Background: Prader Willi Syndrome (PWS) is a genetic disorder caused by the absence of expression of the paternal copies of maternally imprinted gene(s) located at 15q11–q13. While the physical and medical characteristics of PWS, including short stature, hyperphagia and endocrine dysfunction are wel...

Neuropsychiatric features of Prader–Willi syndrome.

Prader–Willi syndrome (PWS) is a genetic disorder characterized by hypotonia and poor feeding in infancy which progresses to hyperphagia in early-mid childhood, as well as developmental delays, a spectrum of behavioral and psychiatric concerns, endocrinopathies, orthopedic issues, and less commonly,...

Feasibility of Screening for Chromosome 15 Imprinting Disorders in 16 579 Newborns by Using a Novel Genomic Workflow

Importance Newborn screening for Angelman syndrome (AS), Prader-Willi syndrome (PWS), and chromosome 15 duplication syndrome (Dup15q) may lead to benefit from early diagnosis and treatment. Objective To examine the feasibility of newborn screening for these chromosome 15 imprinting disorders at popu...

Principles of Genomic Newborn Screening Programs: A Systematic Review.

Importance Genomic newborn screening (gNBS) may optimize the health and well-being of children and families. Screening programs are required to be evidence based, acceptable, and beneficial. Objectives To identify what has been discovered following the reporting of the first gNBS pilot projects and ...

Effects of Transcranial Direct Current Stimulation (tDCS) on Go/NoGo Performance Using Food and Non-Food Stimuli in Patients with Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is a neurodevelopmental genetic disorder characterized by multiple system involvement with hypotonia, poor suck with feeding difficulties, growth and other hormone deficiencies, intellectual disability, and behavioral problems with childhood onset of hyperphagia resulting...

Quantifying the Burden of Hyperphagia in Prader-Willi Syndrome Using Quality-Adjusted Life-years.

Background: Prader-Willi syndrome (PWS) is a rare disease associated with cognitive impairment, hypotonia, hyperphagia (an insatiable hunger), and obesity. Therapies that target hyperphagia are in development, but understanding the value of these therapies to inform patient-focused drug development ...

Measuring Meaningful Benefit-Risk Tradeoffs to Promote Patient-Focused Drug Development in Prader-Willi Syndrome: A Discrete-Choice Experiment

Background. Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder causing quality of life impairments such as insatiable hunger (hyperphagia) and obesity. We explored caregivers’ willingness to assume treatment risk in exchange for reduced hyperphagia according to a PWS-validated observe...

The N-terminal domain of the Schaaf-Yang syndrome protein MAGEL2 likely has a role in RNA metabolism

MAGEL2 encodes the L2 member of the melanoma-associated antigen gene (MAGE) protein family, truncating mutations of which can cause Schaaf-Yang syndrome, an autism spectrum disorder. MAGEL2 is also inactivated in Prader–Willi syndrome, which overlaps clinically and mechanistically with Schaaf–Yang s...

Deficiency of the paternally inherited gene Magel2 alters the development of separation-induced vocalization and maternal behavior in mice

The behavior of offspring results from the combined expression of maternal and paternal genes. Genomic imprinting silences some genes in a parent-of-origin specific manner, a process that, among all animals, occurs only in mammals. How genomic imprinting affects the behavior of mammalian offspring, ...

Molecular Changes in Prader-Willi Syndrome Neurons Reveals Clues About Increased Autism Susceptibility.

Background: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hormonal dysregulation, obesity, intellectual disability, and behavioral problems. Most PWS cases are caused by paternal interstitial deletions of 15q11.2-q13.1, while a smaller number of cases are caused by ch...

Incidence of strabismus, strabismus surgeries, and other vision conditions in Prader-Willi syndrome: data from the Global Prader-Willi Syndrome Registry

Background There is a relative lack of information on the incidence and treatment of vision problems in Prader-Willi syndrome (PWS). Using data from the Global PWS Registry, we performed a cross-sectional study of vision problems in PWS. Methods Data, reported by caregivers who completed the Vision ...

Oxytocin administration in neonates shapes hippocampal circuitry and restores social behavior in a mouse model of autism.

Oxytocin is an important regulator of the social brain. In some animal models of autism, notably in Magel2tm1.1Mus-deficient mice, peripheral administration of oxytocin in infancy improves social behaviors until adulthood. However, neither the mechanisms responsible for social deficits nor the mecha...

The Cost of Raising Individuals with Fragile X or Chromosome 15 Imprinting Disorders in Australia

The study characterised differences in costs associated with raising a child between four rare disorders and examined the associations between these costs with clinical severity. Caregivers of 108 individuals with Prader-Willi, Angelman (AS), Chromosome 15q Duplication and fragile X (FXS) syndromes ...

Visual food cue processing in children with Prader-Willi Syndrome

Hyperphagia and the associated interest in food is a characteristic feature of Prader-Willi syndrome (PWS) that emerges during childhood and remains a life-long concern. This study examined neural responses reflecting food cue salience in children with PWS and typical controls, age 3–12 years. Visua...

Generation of hypothalamic arcuate organoids from human induced pluripotent stem cells

Human brain organoids represent remarkable platforms for recapitulating features of human brain development and diseases. Existing organoid models do not resolve fine brain subregions, such as different nuclei in the hypothalamus. We report the generation of arcuate organoids (ARCOs) from human indu...

Snord116 Post-transcriptionally Increases Nhlh2 mRNA Stability: Implications for Human Prader-Willi Syndrome

The smallest genomic region causing Prader-Willi Syndrome (PWS) deletes the non-coding RNA SNORD116 cluster; however, the function of SNORD116 remains a mystery. Previous work in the field revealed the tantalizing possibility that expression of NHLH2, a gene previously implicated in both obesity and...

Characteristics and relationship between hyperphagia, anxiety, behavioral challenges and caregiver burden in Prader-Willi syndrome

Objectives: Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by maladaptive behaviors, amongst which hyperphagia is a life-long concern for individuals with PWS and their caregivers. The current study examined the contribution of hyperphagia and other factors to caregiver burden ...

Epigenetics in Prader-Willi Syndrome

Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder that affects approximately 1 in 20,000 individuals worldwide. Symptom progression in PWS is classically characterized by two nutritional stages. Stage 1 is hypotonia characterized by poor muscle tone that leads to poor feeding behavio...

Show me what happens next: Preliminary efficacy of a remote play-based intervention for children with Prader-Willi syndrome

Prader-Willi Syndrome (PWS) is characterized by decreased social and emotional functioning. Due to the low base-rate of children with PWS, developing behavioral interventions for individuals with PWS is faced with the challenge of enrolling enough local participants for adequate study of behavioral ...

Functional diversity of small nucleolar RNAs

Small nucleolar RNAs (snoRNAs) are short non-protein-coding RNAs with a long-recognized role in tuning ribosomal and spliceosomal function by guiding ribose methylation and pseudouridylation at targeted nucleotide residues of ribosomal and small nuclear RNAs, respectively. SnoRNAs are increasingly b...

Intranasal oxytocin versus placebo for hyperphagia and repetitive behaviors in children with Prader-Willi Syndrome: A randomized controlled pilot trial

Objective The effects of intranasal oxytocin and placebo on hyperphagia and repetitive behaviors were compared in children and adolescents with Prader Willi Syndrome (PWS). Methods Children and adolescents with PWS were enrolled in an 8-week double-blind placebo-controlled intranasal oxytocin random...

Relationships between UBE3A and SNORD116 expression and features of autism in chromosome 15 imprinting disorders.

Chromosome 15 (C15) imprinting disorders including Prader–Willi (PWS), Angelman (AS) and chromosome 15 duplication (Dup15q) syndromes are severe neurodevelopmental disorders caused by abnormal expression of genes from the 15q11–q13 region, associated with abnormal DNA methylation and/or copy number ...

Re-assessment of the involvement of Snord115 in the serotonin 2C receptor pathway in a genetically relevant mouse model

SNORD115 has been proposed to promote the activity of serotonin (HTR2C) receptor via its ability to base-pair with its pre-mRNA and regulate alternative RNA splicing and/or A-to-I RNA editing. Because SNORD115 genes are deleted in most patients with the Prader-Willi syndrome (PWS), diminished HTR2C ...

IPSC Models of Chromosome 15Q Imprinting Disorders: From Disease Modeling to Therapeutic Strategies

The chromosome 15q11-q13 region of the human genome is regulated by genomic imprinting, an epigenetic phenomenon in which genes are expressed exclusively from one parental allele. Several genes within the 15q11-q13 region are expressed exclusively from the paternally inherited chromosome 15. At leas...

Specific ZNF274 binding interference at SNORD116 activates the maternal transcripts in Prader-Willi syndrome neurons

Prader-Willi syndrome (PWS) is characterized by neonatal hypotonia, developmental delay, and hyperphagia/obesity. This disorder is caused by the absence of paternally-expressed gene products from chromosome 15q11-q13. We previously demonstrated that knocking out ZNF274, a KRAB-domain zinc finger pro...

Emerging roles of the MAGE protein family in stress response pathways

The melanoma antigen (MAGE) proteins all contain a MAGE homology domain (MHD). MAGE genes are conserved in all eukaryotes and have expanded from a single gene in lower eukaryotes to approximately 40 genes in humans and mice. While some MAGEs are ubiquitously expressed in tissues, others are expresse...

Unravelling the Biology of snoRNAs Implicated in Prader-Willi syndrome

Prader-Willi Syndrome is a rare genetic neurodevelopmental disorder that gives rise to a vast array of symptoms which affect the individual from birth. There is currently no cure for Prader-Willi Syndrome. Professor Gordon Carmichael and his team from the Department of Genetics and Genome Sciences a...

Prader-Willi syndrome: reflections on seminal studies and future therapies

Prader-Willi syndrome (PWS) is caused by the loss of function of the paternally inherited 15q11-q13 locus. This region is governed by genomic imprinting, a phenomenon in which genes are expressed exclusively from one parental allele. The genomic imprinting of the 15q11-q13 locus is established in th...

Variability and change over time of weight and BMI among adolescents and adults with Prader-Willi syndrome: a 6-month text-based observational study

Background: Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder in which hyperphagia (excessive appetite) is a hallmark feature. Understanding how weight changes over time in this population is important for capturing the contemporary natural history of the disorder as well as assessin...

Loss of MAGEL2 in Prader-Willi syndrome leads to decreased secretory granule and neuropeptide production

Prader-Willi syndrome (PWS) is a developmental disorder caused by loss of maternally imprinted genes on 15q11-q13, including melanoma antigen gene family member L2 (MAGEL2). The clinical phenotypes of PWS suggest impaired hypothalamic neuroendocrine function; however, the exact cellular defects are ...

Dietary macronutrient regulation of acyl and desacyl ghrelin concentrations in children with Prader-Willi syndrome (PWS)

Background The effects of dietary macronutrients on orexigenic and anorexigenic hormones in children are poorly understood. Objective To explore effects of varying dietary macronutrients on appetite‐regulating hormones [acyl ghrelin (AG) and desacyl ghrelin (DAG), glucagon‐like peptide 1 (GLP‐1), pe...

The modified Atkins diet in children with Prader-Willi syndrome

Background: Prader-Willi Syndrome (PWS) is the most common genetic cause of obesity. Various dietary strategies have been used for weight management for people with PWS. Methods: This was a clinical feasibility study to test the use of the Modified Atkins Diet (low carbohydrate and high fat) for chi...

Loss of Snord116 impacts lateral hypothalamus, sleep and food-related behaviors

Imprinted genes are highly expressed in the hypothalamus; however, whether specific imprinted genes affect hypothalamic neuromodulators and their functions is unknown. It has been suggested that Prader–Willi syndrome (PWS), a neurodevelopmental disorder caused by lack of paternal expression at chrom...

Neural Circuit Mechanism Underlying the Feeding Controlled by Insula-Central Amygdala Pathway

The Central nucleus of amygdala (CeA) contains distinct populations of neurons that play opposing roles in feeding. The circuit mechanism of how CeA neurons process information sent from their upstream inputs to regulate feeding is still unclear. Here we show that activation of the neural pathway pr...

Eye tracking as an objective measure of hyperphagia in children with Prader-Willi syndrome

This study examined sensitivity of eye tracking measures to hyperphagia severity in Prader-Willi syndrome (PWS). Gaze data were collected in 57 children with PWS, age 3-11 years, and 47 typically developing peers at two study sites during free visual exploration of complex stimulus arrays that inclu...

Preliminary Characterization of Parent-Child Interaction in Preschoolers With Prader-Willi Syndrome: The Relationship Between Engagement and Parental Stress

Early parent-child interactions (PCI) impact social cognitive development. Relatedly, children with various developmental disorders exhibit abnormal parental attachment relationships. Parental characteristics and behaviors can impact PCI and socioemotional development as well. No research has examin...

Comparison of Hip and Knee Arthroplasty Rates of Individuals With and Without Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is a complex genetic condition, affecting between 1:10,000 and 1:30,000. The prevalence of hip dysplasia in children with PWS is reportedly between 8% and 30%, but the long-term consequences of residual hip dysplasia remain largely unknown in this population. The purpose ...

A study of voice and non-voice processing in Prader-Willi syndrome

Background Prader-Willi syndrome (PWS) is a rare and complex neurodevelopmental disorder of genetic origin. It manifests itself in endocrine and cognitive problems, including highly pronounced hyperphagia and severe obesity. In many cases, impaired acquisition of social and communication skills lead...

Food and Non-Food-Related Behavior across Settings in Children with Prader–Willi Syndrome

Prader-Willi syndrome (PWS) is characterized by neonatal hypotonia, developmental delay and hyperphagia/obesity and is caused by the absence of paternal contribution to chromosome 15q11-q13. Using induced pluripotent stem cell (iPSC) models of PWS, we previously discovered an epigenetic complex that...

Transcutaneous vagus nerve stimulation (t-VNS): A novel effective treatment for temper outbursts in adults with Prader-Willi Syndrome indicated by results from a non-blind study.

Temper outbursts are a severe problem for people with Prader-Willi Syndrome (PWS). Previous reports indicate that vagus nerve stimulation (VNS) may reduce maladaptive behaviour in neurodevelopmental disorders, including PWS. We systematically investigated the effectiveness of transcutaneous VNS (t-V...

Face processing and exploration of social signals in Prader-Willi syndrome: a genetic signature

Background Faces are critical social cues that must be perfectly processed in order to engage appropriately in everyday social interactions. In Prader-Willi Syndrome (PWS), a rare genetic disorder characterized by cognitive and behavioural difficulties including autism spectrum disorder, the literat...

Ghrelin Receptor Agonist Rescues Excess Neonatal Mortality in a Prader-Willi Syndrome Mouse Model

In the current study, we sought to determine the significance of the ghrelin system in Prader-Willi Syndrome (PWS). PWS is characterized by hypotonia and difficulty feeding in neonates and hyperphagia and obesity beginning later in childhood. Other features include low GH, neonatal hypoglycemia, hyp...

Wired for eating: how is an active feeding circuitry established in the postnatal brain?

From birth, mammals have to find food and maximize caloric intake to ensure growth and survival. Suckling must be initiated quickly after birth and then maintained and controlled until weaning. It is a complex process involving interactions between sensory and motor neuronal pathways. Meanwhile, the...

Magel2 Modulates Bone Remodeling and Mass in Prader-Willi Syndrome by Affecting Oleoyl Serine Levels and Activity

Among a multitude of hormonal and metabolic complications, individuals with Prader‐Willi syndrome (PWS) exhibit significant bone abnormalities, including decreased BMD, osteoporosis, and subsequent increased fracture risk. Here we show in mice that loss of Magel2, a maternally imprinted gene in the ...

Dietary intake in youth with prader-willi syndrome

Dietary management is important to prevent severe obesity in individuals with Prader‐Willi syndrome (PWS); however, few studies have examined dietary intake and quality in youth with PWS. Our objective was to estimate intake of essential nutrients and diet quality in youth with PWS compared to those...

Caregiver priorities for endpoints to evaluate treatments for Prader-Willi syndrome: a best-worst scaling

The PRETEND Program: Evaluating the Feasibility of a Remote Parent-Training Intervention for Children With Prader-Willi Syndrome

Research has shown that children with Prader-Willi syndrome (PWS) have social-cognitive challenges and decreased quality parent-child interactions. However, given the low prevalence rate, developing interventions for children with PWS is faced with the significant challenge of enrolling enough parti...

Schaaf-Yang syndrome overview: Report of 78 individuals

Schaaf‐Yang Syndrome (SYS) is a genetic disorder caused by truncating pathogenic variants in the paternal allele of the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader‐Willi critical region 15q11‐15q13. SYS is a neurodevelopmental disorder that has clinical overlap with...

Sex and gender differences in developmental programming of metabolism

Background: The early life environment experienced by an individual in utero and during the neonatal period is a major factor in shaping later life disease risk-including susceptibility to develop obesity, diabetes, and cardiovascular disease. The incidence of metabolic disease is different between ...

Functional group and stereochemical requirements for substrate binding by ghrelin O-acyltransferase revealed by unnatural amino acid incorporation

Ghrelin is a small peptide hormone that undergoes a unique posttranslational modification, serine octanoylation, to play its physiological roles in processes including hunger signaling and glucose metabolism. Ghrelin O-acyltransferase (GOAT) catalyzes this posttranslational modification, which is es...

Prader-Willi locus Snord116 RNA processing requires an active endogenous allele and neuron-specific splicing by Rbfox3/NeuN

Prader-Willi syndrome (PWS), an imprinted neurodevelopmental disorder characterized by metabolic, sleep and neuropsychiatric features, is caused by the loss of paternal SNORD116, containing only non-coding RNAs (ncRNAs). The primary SNORD116 transcript is processed into small nucleolar RNAs (snoRNAs...

Exploring autism symptoms in an Australian cohort of patients with Prader-Willi and Angelman syndromes

Background Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurodevelopmental disorders that are caused by abnormal expression of imprinted genes in the 15q11-13 region. Dysregulation of genes located in this region has been proposed as a susceptibility factor for autism spectrum disorder...

The posterior pituitary expresses the serotonin receptor 2C

The serotonin receptor 2C (5HT2C) is an important drug target to treat obesity and depression. Its pre-mRNA undergoes alternative splicing, encoding a short RNA1 isoform that is localized intracellularly and a full-length isoform (RNA2) that can reach the cell membrane. These splicing isoforms are d...

Hormonal and metabolic effects of carbohydrate restriction in children with Prader Willi syndrome

Objective Macronutrient regulation of hyperphagia and adiposity in Prader‐Willi syndrome (PWS) is poorly understood. We compared fasting and postprandial concentrations of hormones and metabolites in eight PWS children (age 9‐18 years) fed, in random order, low carbohydrate, high‐fat (LC, 15% carb; ...

Genomic imprinting and the control of sleep in mammals

Recent epigenetic studies suggest that genomic imprinting is crucial in the biology of sleep. Sleep is a physiological process that is governed by homeostatic and circadian mechanisms, and here we review evidence that both mechanisms are influenced by imprinted regulatory processes. A growing number...

Imprinted small noncoding RNA genes in brain function and behavior

The imprinted DLK1-DIO3 and SNURF-SNRPN (PWS) chromosomal domains are characterized by large arrays of box C/D small nucleolar RNA and microRNA genes that display preferential expression in the brain. Here, we provide an overview of their multifaceted roles in brain function and behaviour focusing p...

Developing a Task Switching Training Game for Children With a Rare Genetic Syndrome Linked to Intellectual Disability

Background. The ability to rapidly switch between tasks is important in a variety of contexts. Training in task switching may be particularly valuable for children with intellectual disability (ID), specifically ID linked to genetic syndromes such as Prader-Willi syndrome (PWS). We have developed a ...

Regulation of Energy Expenditure by Brainstem GABA Neurons

Homeostatic control of core body temperature is essential for survival. Temperature is sensed by specific neurons, in turn eliciting both behavioral (i.e., locomotion) and physiologic (i.e., thermogenesis, vasodilatation) responses. Here, we report that a population of GABAergic (Vgat-expressing) ne...

Potential of Epigenetic Therapy for Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is a neurobehavioral and epigenetic disorder caused by the deficiency of paternally expressed genes in the chromosome 15q11-q13. This unique molecular defect renders PWS an exciting opportunity to explore epigenetic therapy. Here, we briefly highlight recent findings from...

A randomized pilot efficacy and safety trial of diazoxide choline controlled-release in patients with Prader-Willi syndrome

Introduction Prader-Willi syndrome (PWS) is a complex genetic condition characterized by hyperphagia, hypotonia, low muscle mass, excess body fat, developmental delays, intellectual disability, behavioral problems, and growth hormone deficiency. This study evaluated the safety and efficacy of orally...

Epigenetics of Circadian Rhythms in Imprinted Neurodevelopmental Disorders

DNA sequence information alone cannot account for the immense variability between chromosomal alleles within diverse cell types in the brain, whether these differences are observed across time, cell type, or parental origin. The complex control and maintenance of gene expression and modulation are r...

A Transcriptomic Signature of the Hypothalamic Response to Fasting and BDNF Deficiency in Prader-Willi Syndrome

Transcriptional analysis of brain tissue from people with molecularly defined causes of obesity may highlight disease mechanisms and therapeutic targets. We performed RNA sequencing of hypothalamus from individuals with Prader-Willi syndrome (PWS), a genetic obesity syndrome characterized by severe ...

Mechanistic insights into the genetics of affective psychosis from Prader-Willi syndrome

Schizophrenia and bipolar disorder are common, severe, and disabling psychotic disorders, which are difficult to research. We argue that the genetically determined neurodevelopmental disorder Prader-Willi syndrome (PWS), which is associated with a high risk of affective psychotic illness, can provid...

Chronic diazoxide treatment decreases fat mass and improves endurance capacity in an obese mouse model of Prader-Willi syndrome

Excess fat mass is a cardinal feature of Prader-Willi syndrome (PWS) that is recapitulated in the Magel2-null mouse model of this genetic disorder. There is a pressing need for drugs that can prevent or treat obesity in children with PWS. Recently, a clinical study of a controlled release form of th...

High levels of caregiver burden in Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder that is characterized by hyperphagia, developmental delay, incomplete sexual development, mild-to-moderate intellectual disability, and a variety of challenging behavioral and psychiatric symptoms. The characteristics of PWS c...

Neuronal differentiation induces SNORD115 expression and is accompanied by post-transcriptional changes of serotonin receptor 2c mRNA

The serotonin neurotransmitter system is widespread in the brain and implicated in modulation of neuronal responses to other neurotransmitters. Among 14 serotonin receptor subtypes, 5-HT2cR plays a pivotal role in controlling neuronal network excitability. Serotonergic activity conveyed through rece...

Hormonal, metabolic and skeletal phenotype of Schaaf-Yang syndrome: a comparison to Prader-Willi syndrome

BACKGROUND: Nonsense and frameshift mutations in the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader-Willi critical region 15q11-15q13, have been reported to cause Schaaf-Yang syndrome (SYS), a genetic disorder that manifests as developmental delay/intellectual disabili...

Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome

Profound hyperphagia is a major disabling feature of Prader-Willi syndrome (PWS). Characterization of the mechanisms that underlie PWS-associated hyperphagia has been slowed by the paucity of animal models with increased food intake or obesity. Mice with a microdeletion encompassing the Snord116 clu...

Zinc finger protein 274 regulates imprinted expression of transcripts in Prader-Willi syndrome neurons

Prader-Willi syndrome (PWS) is characterized by neonatal hypotonia, developmental delay and hyperphagia/obesity and is caused by the absence of paternal contribution to chromosome 15q11-q13. Using induced pluripotent stem cell (iPSC) models of PWS, we previously discovered an epigenetic complex that...

Phylogenetic Analysis of the SNORD116 Locus

The SNORD116 small nucleolar RNA locus ( SNORD116@) is contained within the long noncoding RNA host gene SNHG14 on human chromosome 15q11-q13. The SNORD116 locus is a cluster of 28 or more small nucleolar (sno) RNAs; C/D box (SNORDs). Individual RNAs within the cluster are tandem, highly similar seq...

Loss of the imprinted, non-coding Snord116 gene cluster in the interval deleted in the Prader Willi syndrome results in murine neuronal and endocrine pancreatic developmental phenotypes

Global neurodevelopmental delay is a prominent characteristic of individuals with Prader-Willi syndrome (PWS). The neuromolecular bases for these delays are unknown. We identified neuroanatomical changes in the brains of mice deficient for a gene in the minimal critical deletion region for PWS (Snor...

Dental pulp stem cells for the study of neurogenetic disorders

Dental pulp stem cells (DPSC) are a relatively new alternative stem cell source for the study of neurogenetic disorders. DPSC can be obtained non-invasively and collected from long-distances remaining viable during transportation. These highly proliferative cells express stem cell markers and retain...

Microstructural white matter tract alteration in Prader-Willi syndrome: A diffusion tensor imaging study

Prader-Willi Syndrome (PWS) is a genetic disorder characterized by infantile hypotonia, hyperphagia, hypogonadism, growth hormone deficiency, intellectual disability, and severe emotional and behavioral problems. The brain mechanisms that underpin these disturbances are unknown. Diffusion tensor ima...

Aberrant White Matter Microstructure in Children and Adolescents With the Subtype of Prader-Willi Syndrome at High Risk for Psychosis

Prader-Willi Syndrome (PWS) is a complex neurogenetic disorder caused by loss of the paternal 15q11.2-q13 locus, due to deletion (DEL), maternal uniparental disomy (mUPD), or imprinting center defects. Individuals with mUPD have up to 60% risk of developing psychosis in early adulthood. Given the in...

PREPL deficiency: delineation of the phenotype and development of a functional blood assay

Purpose: PREPL deficiency causes neonatal hypotonia, ptosis, neonatal feeding difficulties, childhood obesity, xerostomia, and growth hormone deficiency. Different recessive contiguous gene deletion syndromes involving PREPL and a variable combination of SLC3A1 (hypotonia-cystinuria syndrome), CAMKM...

Cataplexy and Its Mimics: Clinical Recognition and Management

OPINION STATEMENT: This review describes the diagnosis and management of cataplexy: attacks of bilateral loss of muscle tone, triggered by emotions and with preserved consciousness. Although cataplexy is rare, its recognition is important as in most cases, it leads to a diagnosis of narcolepsy, a di...

C/D-box snoRNAs form methylating and non-methylating ribonucleoprotein complexes: Old dogs show new tricks

C/D box snoRNAs (SNORDs) are an abundantly expressed class of short, non-coding RNAs that have been long known to perform 2'-O-methylation of rRNAs. However, approximately half of human SNORDs have no predictable rRNA targets, and numerous SNORDs have been associated with diseases that show no defec...

The activity of the serotonin receptor 2C is regulated by alternative splicing

The central nervous system-specific serotonin receptor 2C (5HT2C) controls key physiological functions, such as food intake, anxiety, and motoneuron activity. Its deregulation is involved in depression, suicidal behavior, and spasticity, making it the target for antipsychotic drugs, appetite control...

Cellular and disease functions of the Prader-Willi Syndrome gene MAGEL2

Melanoma antigen L2 (MAGEL2 or MAGE-L2) is a member of the MAGE family of ubiquitin ligase regulators. It is maternally imprinted and often paternally deleted or mutated in the related neurodevelopmental syndromes, Prader-Willi Syndrome (PWS) and Schaaf-Yang Syndrome (SHFYNG). MAGEL2 is highly expre...

Autism spectrum disorder: neuropathology and animal models

Autism spectrum disorder (ASD) has a major impact on the development and social integration of affected individuals and is the most heritable of psychiatric disorders. An increase in the incidence of ASD cases has prompted a surge in research efforts on the underlying neuropathologic processes. We p...

A Comprehensive Guide to the MAGE Family of Ubiquitin Ligases

Melanoma antigen (MAGE) genes are conserved in all eukaryotes and encode for proteins sharing a common MAGE homology domain. Although only a single MAGE gene exists in lower eukaryotes, the MAGE family rapidly expanded in eutherians and consists of more than 50 highly conserved genes in humans. A su...

Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome

Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central hypogonadism, and low growth hormone (GH). Rare microdeletions in PWS patients define a 91-kb minimum critical d...

Determination of the half-life of circulating leptin in the mouse

BACKGROUND: The adipokine hormone, leptin, is a major component of body weight homeostasis. Numerous studies have been performed administering recombinant mouse leptin as an experimental reagent; however, the half-life of circulating leptin following exogenous administration of recombinant mouse lep...

Altered functional resting-state hypothalamic connectivity and abnormal pituitary morphology in children with Prader-Willi syndrome

BACKGROUND: Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder, characterized by endocrine problems and hyperphagia, indicating hypothalamic-pituitary dysfunction. However, few studies have explored the underlying neurobiology of the hypothalamus and its functional connectivity wit...

PC1/3 Deficiency Impacts Pro-opiomelanocortin Processing in Human Embryonic Stem Cell-Derived Hypothalamic Neurons

We recently developed a technique for generating hypothalamic neurons from human pluripotent stem cells. Here, as proof of principle, we examine the use of these cells in modeling of a monogenic form of severe obesity: PCSK1 deficiency. The cognate enzyme, PC1/3, processes many prohormones in neuroe...

Culturing and Neuronal Differentiation of Human Dental Pulp Stem Cells

A major issue in studying human neurogenetic disorders, especially rare syndromes affecting the nervous system, is the ability to grow neuronal cultures that accurately represent these disorders for analysis. Although there has been some success in generating induced pluripotent stem (iPS) cells fro...

Targeting the histone methyltransferase G9a activates imprinted genes and improves survival of a mouse model of Prader–Willi syndrome

This publication was highlighted in an FPWR Research Blog post "Promising First Steps Towards Genetic Therapy for Prader-Willi Syndrome" (December 2016) Prader–Willi syndrome (PWS) is an imprinting disorder caused by a deficiency of paternally expressed gene(s) in the 15q11–q13 chromosomal region. T...

Dysfunctional oleoylethanolamide signaling in a mouse model of Prader-Willi syndrome

Prader-Willi syndrome (PWS), the leading genetic cause of obesity, is characterized by a striking hyperphagic behavior that can lead to obesity, type-2 diabetes, cardiovascular disease and death. The molecular mechanism underlying impaired satiety in PWS is unknown. Oleoylethanolamide (OEA) is a lip...

Paradoxical Leanness in the Imprinting Centre Deletion Mouse Model for Prader-Willi Syndrome

Prader-Willi syndrome (PWS), a neurodevelopmental disorder caused by loss of paternal gene expression from 15q11-q13, is characterised by growth retardation, hyperphagia, and obesity. However, since single gene mutation mouse models for this condition display an incomplete spectrum of the PWS phenot...

Induced pluripotent stem cells (iPSC) created from skin fibroblasts of patients with Prader-Willi syndrome (PWS) retain the molecular signature of PWS

Prader-Willi syndrome (PWS) is a syndromic obesity caused by loss of paternal gene expression in an imprinted interval on 15q11.2-q13. Induced pluripotent stem cells were generated from skin cells of three large deletion PWS patients and one unique microdeletion PWS patient. We found that genes with...

Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader-Willi syndrome

OBJECTIVE: Extreme obesity is a core phenotypic feature of Prader-Willi syndrome (PWS). Among numerous metabolic regulators, the endocannabinoid (eCB) system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB1R) blockad...

Muscle dysfunction caused by loss of Magel2 in a mouse model of Prader-Willi and Schaaf-Yang syndromes

Prader-Willi syndrome is characterized by severe hypotonia in infancy, with decreased lean mass and increased fat mass in childhood followed by severe hyperphagia and consequent obesity. Scoliosis and other orthopaedic manifestations of hypotonia are common in children with Prader-Willi syndrome and...

Oligonucleotide-induced alternative splicing of serotonin 2C receptor reduces food intake

The serotonin 2C receptor regulates food uptake, and its activity is regulated by alternative pre-mRNA splicing. Alternative exon skipping is predicted to generate a truncated receptor protein isoform, whose existence was confirmed with a new antiserum. The truncated receptorsequesters the full-leng...

Reduced Gamma-Aminobutyric Acid Is Associated With Emotional and Behavioral Problems in Prader–Willi Syndrome

Prader-Willi syndrome (PWS) is characterized by infantile hypotonia, hypogonadism, small hands and feet, distinct facial features and usually intellectual impairment. The disorder is associated with severe behavioral disturbances which include hyperphagia leading to morbid obesity, temper outbursts,...

Efficient Generation of Hypothalamic Neurons from Human Pluripotent Stem Cells

The hypothalamus comprises neuronal clusters that are essential for body weight regulation and other physiological functions. Insights into the complex cellular physiology of this region of the brain are critical to understanding the pathogenesis of obesity, but human hypothalamic cells are largely ...

Loss of Magel2 Impairs the Development of Hypothalamic Anorexigenic Circuits

Prader-Willi syndrome (PWS) is a genetic disorder characterized by a variety of physiological and behavioral dysregulations, including hyperphagia, a condition that can lead to life-threatening obesity. Feeding behavior is a highly complex process with multiple feedback loops that involve both perip...

The phenotypic spectrum of Schaaf-Yang syndrome: 18 new affected individuals from 14 families

PURPOSE: Truncating mutations in the maternally imprinted, paternally expressed gene MAGEL2, which is located in the Prader-Willi critical region 15q11-13, have recently been reported to cause Schaaf-Yang syndrome, a Prader-Willi-like disease that manifests as developmental delay/intellectual disabi...

Lateral Hypothalamic Area Glutamatergic Neurons and Their Projections to the Lateral Habenula Regulate Feeding and Reward

The overconsumption of calorically dense, highly palatable foods is thought to be a major contributor to the worldwide obesity epidemic; however, the precise neural circuits that directly regulate hedonic feeding remain elusive. Here, we show that lateral hypothalamic area (LHA) glutamatergic neuron...

Nutritional Phases in Prader-Willi Syndrome: Evolutionary and Clinical Interpretations

Prader-Willi syndrome (PWS) is caused by a lack of expression of paternally-expressed imprinted genes at human chromosome 15q11-13 and is characterized by a switch from infant anorexia to childhood hyperphagia. A recent multiphase staging system recognizes gradual changes between the anorexic and hy...

High unacylated ghrelin levels support the concept of anorexia in infants with prader-willi syndrome

BACKGROUND: Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with different nutritional phases from suckling deficit with failure to thrive to early onset of obesity. Hyperghrelinemia has been described in PWS long before the development of obesity. Ghrelin is found in both ...

Monogenic mouse models of autism spectrum disorders: Common mechanisms and missing links

Autism spectrum disorders (ASDs) present unique challenges in the fields of genetics and neurobiology because of the clinical and molecular heterogeneity underlying these disorders. Genetic mutations found in ASD patients provide opportunities to dissect the molecular and circuit mechanisms underlyi...

Dual function of C/D box small nucleolar RNAs in rRNA modification and alternative pre-mRNA splicing

C/D box small nucleolar RNAs (SNORDs) are small noncoding RNAs, and their best-understood function is to target the methyltransferase fibrillarin to rRNA (for example, SNORD27 performs 2'-O-methylation of A27 in 18S rRNA). Unexpectedly, we found a subset of SNORDs, including SNORD27, in soluble nucl...

Progress in Small Molecule and Biologic Therapeutics Targeting Ghrelin Signaling

Ghrelin is a circulating peptide hormone involved in regulation of a wide array of physiological processes. As an endogenous ligand for growth hormone secretagogue receptor (GHS-R1a), ghrelin is responsible for signaling involved in energy homeostasis, including appetite stimulation, glucose metabol...

Novel Regulator of Acylated Ghrelin, CF801, Reduces Weight Gain, Rebound Feeding after a Fast, and Adiposity in Mice

Ghrelin is a 28 amino acid hormonal peptide that is intimately related to the regulation of food intake and body weight. Once secreted, ghrelin binds to the growth hormone secretagogue receptor-1a, the only known receptor for ghrelin and is capable of activating a number of signaling cascades, ultim...

Autism spectrum disorder in Prader-Willi syndrome: A systematic review

Prader-Willi syndrome (PWS) is a rare genetic disorder that results from lack of expression of paternally-derived genes on chromosome 15q11-13; caused by a deletion (DEL), uniparental disomy (UPD), or a rare imprinting center defect. PWS is associated with a distinct behavioral phenotype that in som...

A review of chemosensory perceptions, food preferences and food-related behaviours in subjects with Prader-Willi Syndrome

Hyperphagia and obsessive preoccupation with food are hallmark characteristics of Prader-Willi Syndrome (PWS). Although hyperphagia in PWS is linked to hypothalamic dysfunction, the underlying mechanisms behind this problem are poorlyunderstood. Moreover, our understanding of howchemosensory percept...

Lateral hypothalamic circuits for feeding and reward

In experiments conducted over 60 years ago, the lateral hypothalamic area (LHA) was identified as a critical neuroanatomical substrate for motivated behavior. Electrical stimulation of the LHA induces voracious feeding even in well-fed animals. In the absence of food, animals will work tirelessly, o...

Obesity Impairs the Action of the Neuroendocrine Ghrelin System

Ghrelin is a metabolic hormone that promotes energy conservation by regulating appetite and energy expenditure. Although some studies suggest that antagonizing ghrelin function attenuates body weight gain and glucose intolerance on a high calorie diet, there is little information about the metabolic...

Insulin-driven translational capacity is impaired in primary fibroblasts of Prader Willi

Prader-Willi (PW) syndrome is a rare genetic disorder characterized by hypothalamic-pituitary abnormalities and severe hypotonia, hyperphagia, behavioural and psychiatric problems. Absence of satiety leads to severe obesity and frequently to diabetes. Furthermore, adult patients suffer from a severe...

USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder

Endosomal protein recycling is a fundamental cellular process important for cellular homeostasis, signaling, and fate determination that is implicated in several diseases. WASH is an actin-nucleating protein essential for this process, and its activity is controlled through K63-linked ubiquitination...

Neural correlates of self-injurious behavior in Prader-Willi syndrome

Individuals with Prader-Willi syndrome (PWS), a genetic disorder caused by mutations to the q11-13 region on chromosome 15, commonly show severe skin-picking behaviors that can cause open wounds and sores on the body. To our knowledge, however, no studies have examined the potential neural mechanism...

Sexual dichotomy of gonadal function in Prader-Willi syndrome from early infancy through the fourth decade

STUDY QUESTION: At what age does the type of hypogonadism, namely hypothalamic or primary gonadal defect, become established in men and women with Prader-Willi syndrome (PWS)? SUMMARY ANSWER: The type of hypogonadism becomes established only in late adolescence and early adulthood. WHAT IS KNOWN ALR...

Epigenetic mechanisms in diurnal cycles of metabolism and neurodevelopment

The circadian cycle is a genetically encoded clock that drives cellular rhythms of transcription, translation and metabolism. The circadian clock interacts with the diurnal environment that also drives transcription and metabolism during light/dark, sleep/wake, hot/cold and feast/fast daily and seas...

Macronutrient regulation of Ghrelin and Peptide YY in Pediatric Obesity and Prader Willi Syndrome (PWS)

BACKGROUND: The roles of macronutrients and GH in the regulation of food intake in pediatric obesity and PWS are poorly understood. OBJECTIVE: We compared effects of high carbohydrate (HC) and high fat (HF) meals and GH therapy on ghrelin, insulin, PYY, and insulin sensitivity in children with PWS a...

SNORD116 and SNORD115 change expression of multiple genes and modify each other's activity

The loss of two gene clusters encoding small nucleolar RNAs, SNORD115 and SNORD116 contribute to Prader-Willi syndrome (PWS), the most common syndromic form of obesity in humans. SNORD115 and SNORD116 are considered to be orphan C/D box snoRNAs (SNORDs) as they do not target rRNAs or snRNAs. SNORD11...

Metabolic profiling in Prader-Willi syndrome and nonsyndromic obesity: sex differences and the role of growth hormone

OBJECTIVES: To identify metabolic factors controlling appetite and insulin sensitivity in PWS and assess effects of GH treatment. METHODS: We compared amino acids, fatty acids and acylcarnitines in GH-treated and untreated PWS children and obese and lean controls to identify biomarkers associated wi...

A new class of ghrelin O-acyltransferase inhibitors incorporating triazole-linked lipid mimetic groups

Inhibitors of ghrelin O-acyltransferase (GOAT) have untapped potential as therapeutics targeting obesity and diabetes. We report the first examples of GOAT inhibitors incorporating a triazole linkage as a biostable isosteric replacement for the ester bond in ghrelin and amide bonds in previously rep...

Progressive postnatal decline in leptin sensitivity of arcuate hypothalamic neurons in the Magel2-null mouse model of Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is a multigene disorder associated with neonatal failure to thrive, developmental delay, and endocrine abnormalities suggestive of hypothalamic dysfunction. Children with PWS typically develop overt hyperphagia and obesity around 8 years of age, later than children with o...

Metabolic profiling in Prader-Willi syndrome and non-syndromic obesity: sex differences and the role of growth hormone

OBJECTIVES: To identify metabolic factors controlling appetite and insulin sensitivity in PWS and assess effects of GH treatment. METHODS: We compared amino acids, fatty acids, and acylcarnitines in GH-treated and untreated PWS children and obese and lean controls to identify biomarkers associated w...

Ageing in people with Prader-Willi syndrome: mortality in the UK population cohort and morbidity in an older sample of adults

BACKGROUND: The past two decades have seen a great improvement in the care of people with Prader-Willi syndrome (PWS), particularly with regard to control of diet and behaviour management. Has this affected mortality rates or thrown up new issues regarding premature ageing or dementia? We investigat...

Chemical identity of hypothalamic neurons engaged by leptin in reproductive control

The adipocyte-derived hormone leptin plays a critical role as a metabolic cue for the reproductive system. Conditions of low leptin levels observed in negative energy balance and loss-of-function mutations of leptin or leptin receptor genes are characterized by decreased fertility. In recent years, ...

Estradiol modulates Kiss1 neuronal response to ghrelin

Ghrelin is a metabolic signal regulating energy homeostasis. Circulating ghrelin levels rise during starvation and fall after a meal, and therefore, ghrelin may function as a signal of negative energy balance. Ghrelin may also act as a modulator of reproductive physiology, as acute ghrelin administr...

Hyperphagia: Current concepts and future directions proceedings of the 2nd international conference on hyperphagia

Objective Hyperphagia is a central feature of inherited disorders (e.g., Prader–Willi Syndrome) in which obesity is a primary phenotypic component. Hyperphagia may also contribute to obesity as observed in the general population, thus raising the potential importance of common underlying mechanisms ...

Neonatal overnutrition causes early alterations in the central response to peripheral ghrelin

Objective Excess nutrient supply and rapid weight gain during early life are risk factors for the development of obesity during adulthood. This metabolic malprogramming may be mediated by endocrine disturbances during critical periods of development. Ghrelin is a metabolic hormone secreted from the ...

A critical view of the use of genetic tools to unveil neural circuits: the case of leptin action in reproduction

The remarkable development and refinement of the Cre-loxP system coupled with the nonstop production of new mouse models and virus vectors have impelled the growth of various fields of investigation. In this article, I will discuss the data collected using these genetic tools in our area of interest...

Longitudinal Study of Reproductive Hormones in Prader-Willi Syndrome (PWS) from Early Infancy through the Fourth Decade

Background: We previously showed in cross-sectional studies of PWS men (1) and women (2) that the etiology of hypogonadism is heterogeneous, with primary testicular failure common in PWS men and variable combinations of ovarian dysfunction and gonadotropin deficiency in women. Longitudinal studies c...

CRF type 2 receptors mediate the metabolic effects of ghrelin in C2C12 cells

Ghrelin is known to regulate appetite control and cellular metabolism. The corticotropin-releasing factor (CRF) family is also known to regulate energy balance. In this study, the links between ghrelin and the CRF family in C2C12 cells, a mouse myoblast cell line was investigated. Design and Methods...

Abdominal Leanness in the Imprinting Center-Deletion Mouse Model for Prader-Willi Syndrome May Result from Excess Thermogenesis

Prader–Willi syndrome (PWS) is a neurodevelopmental disorder caused by a lack of paternal gene expression from 15q11–q13 and is characterized by a failure to thrive in infancy, followed by impaired skeletal growth, hyperghrelinemia, reduced satiety responses, hyperphagia and obesity. We have shown t...

Neuropeptide Y Activity in the Nucleus Accumbens Modulates Feeding Behavior and Neuronal Activity

BACKGROUND: Neuropeptide Y (NPY) is a hypothalamic neuropeptide that plays a prominent role in feeding and energy homeostasis. Expression of the NPY Y1 receptor (Y1R) is highly concentrated in the nucleus accumbens (Acb), a region important in the regulation of palatable feeding. In this study, we p...

Structure-activity analysis of human ghrelin o-acyltransferase reveals chemical determinants of ghrelin selectivity and acyl group recognition

Ghrelin O-acyltransferase (GOAT) is an integral membrane acyltransferase responsible for catalyzing a serine-octanoylation posttranslational modification within the peptide hormone ghrelin. Ghrelin requires this octanoylation for its biological activity in stimulating appetite and in regulating othe...

Gene-Environment Interactions Controlling Energy and Glucose Homeostasis and the Developmental Origins of Obesity

Obesity and type 2 diabetes mellitus (T2DM) often occur together and affect a growing number of individuals in both the developed and developing worlds. Both are associated with a number of other serious illnesses that lead to increased rates of mortality. There is likely a polygenic mode of inherit...

Differentiation of hypothalamic-like neurons from human pluripotent stem cells

The hypothalamus is the central regulator of systemic energy homeostasis, and its dysfunction can result in extreme body weight alterations. Insights into the complex cellular physiology of this region are critical to the understanding of obesity pathogenesis; however, human hypothalamic cells are l...

Neonatal ghrelin programs development of hypothalamic feeding circuits

A complex neural network regulates body weight and energy balance, and dysfunction in the communication between the gut and this neural network is associated with metabolic diseases, such as obesity. The stomach-derived hormone ghrelin stimulates appetite through interactions with neurons in the arc...

Visualizing hypothalamic network dynamics for appetitive and consummatory behaviors

Optimally orchestrating complex behavioral states, such as the pursuit and consumption of food, is critical for an organism's survival. The lateral hypothalamus (LH) is a neuroanatomical region essential for appetitive and consummatory behaviors, but whether individual neurons within the LH differen...

Reduced cortical complexity in children with Prader-Willi syndrome and its association with cognitive impairment and developmental delay

BACKGROUND: Prader-Willi Syndrome (PWS) is a complex neurogenetic disorder with symptoms involving not only hypothalamic, but also a global, central nervous system dysfunction. Previously, qualitative studies reported polymicrogyria in adults with PWS. However, there have been no quantitative neuroi...

Hypoglycemia in Prader-Willi syndrome

Although mouse models of Prader-Willi syndrome (PWS) suggest that hypoglycemia may be part of this syndrome, review of the literature shows little evidence that it is an issue in humans with PWS. Both adrenal and growth hormone deficiency can be seen in PWS, and both of these hormone deficiencies ar...

Abnormal response to the anorexic effect of GHS-R inhibitors and exenatide in male Snord116 deletion mouse model for Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a genetic disease characterized by persistent hunger and hyperphagia. The lack of the Snord116 small nucleolar RNA cluster has been identified as the major contributor to PWS symptoms. The Snord116 deletion (Snord116del) mouse model manifested a subset of PWS symptoms ...

Characterization of minipuberty in infants with Prader-Willi syndrome

Background: Minipuberty describes transient activation of the hypothalamic-pituitary-gonadal axis occurring during the first few months of life. Hormone levels during minipuberty were described in only a few Prader-Willi syndrome (PWS) infant boys and have not been reported in PWS infant girls. Obje...

A double-blind randomized controlled trial of oxytocin nasal spray in Prader Willi syndrome

Individuals with Prader-Willi syndrome (PWS) have a significant reduction in the number of oxytocin-producing neurons (42%) in the hypothalamic paraventricular nucleus. A number of animal studies and observations of humans show that lesions in this region can produce PWS-like symptoms. Given the evi...

Experimental functional analysis of severe skin-picking behavior in Prader–Willi syndrome

Skin picking is an extremely distressing and treatment resistant behavior commonly shown by individuals with Prader–Willi syndrome (PWS). However, with the exception of a limited number of published single-case and survey studies, little is known about the environmental determinants of skin picking ...

Imprinted expression of UBE3A in non-neuronal cells from a Prader-Willi syndrome patient with an atypical deletion

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two neurodevelopmental disorders most often caused by deletions of the same region of paternally inherited and maternally inherited human chromosome 15q, respectively. AS is a single gene disorder, caused by the loss of function of the ubiqu...

Reactivation of Maternal SNORD116 Cluster via SETDB1 knockdown in Prader-Willi Syndrome iPSCs

Prader-Willi syndrome (PWS), a disorder of genomic imprinting, is characterized by neonatal hypotonia, hypogonadism, small hands and feet, hyperphagia and obesity in adulthood. PWS results from the loss of paternal copies of the cluster of SNORD116 C/D box snoRNAs and their host transcript, 116HG, o...

Prader-Willi syndrome, excessive daytime sleepiness, and narcoleptic symptoms: a case report

INTRODUCTION: Sleep abnormalities, including narcolepsy and cataplexy, are a common feature of Prader-Willi syndrome. Long-term treatment with the central nervous system stimulant modafinil has not been reported. In this case report we present a longitudinal perspective of sleep abnormalities in a n...

Kiss of the Mutant Mouse: How Genetically Altered Mice Advanced Our Understanding of Kisspeptin's Role in Reproductive Physiology

The kisspeptin system has emerged as one of the most important circuits within the central network governing reproduction. Although kisspeptin physiology has been examined in many species, much of our understanding of this system has come from mice. Recently, the study of several innovative strains ...

Effects of Adiposity and Prader-Willi Syndrome on Postexercise Heart Rate Recovery

Heart rate recovery (HRR) is an indicator of all-cause mortality in children and adults. We aimed to determine the effect of adiposity and Prader-Willi Syndrome (PWS), a congenital form of obesity, on HRR. Sixteen children of normal weight (NW = body fat % ≤85th percentile, 9.4 ± 1.1 y), 18 children...

Direct cloning of double-stranded RNAs from RNase protection analysis reveals processing patterns of C/D box snoRNAs and provides evidence for widespread antisense transcript expression

We describe a new method that allows cloning of double-stranded RNAs (dsRNAs) that are generated in RNase protection experiments. We demonstrate that the mouse C/D box snoRNA MBII-85 (SNORD116) is processed into at least five shorter RNAs using processing sites near known functional elements of C/D ...

Growth Hormone Research Society workshop summary: consensus guidelines for recombinant human growth hormone therapy in Prader-Willi syndrome.

CONTEXT: Recombinant human GH (rhGH) therapy in Prader-Willi syndrome (PWS) has been used by the medical community and advocated by parental support groups since its approval in the United States in 2000 and in Europe in 2001. Its use in PWS represents a unique therapeutic challenge that includes tr...

Recommendations for the investigation of animal models of Prader-Willi syndrome

Prader-Willi syndrome (PWS) occurs in about 1 in 15,000 individuals and is a contiguous gene disorder causing developmental disability, hyperphagia usually with obesity, and behavioral problems, including an increased incidence of psychiatric illness. The genomic imprinting that regulates allele-spe...

Leptin signaling and circuits in puberty and fertility

Leptin is an adipocyte-derived hormone involved in a myriad of physiological process, including the control of energy balance and several neuroendocrine axes. Leptin-deficient mice and humans are obese, diabetic, and display a series of neuroendocrine and autonomic abnormalities. These individuals a...

Management of hypogonadism in adolescent girls and adult women with Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by an insatiable appetite, dysmorphic features, cognitive and behavioral difficulties, and hypogonadism. The heterogeneous reproductive hormone profiles indicate that some PWS women may have symptoms of hypoestrogenism, while...

Differential gene expression reveals mitochondrial dysfunction in an imprinting center deletion mouse model of prader-willi syndrome

Prader-Willi syndrome (PWS) is a genetic disorder caused by deficiency of imprinted gene expression from the paternal chromosome 15q11-15q13 and clinically characterized by neonatal hypotonia, short stature, cognitive impairment, hypogonadism, hyperphagia, morbid obesity, and diabetes. Previous clin...

R-loop formation at Snord116 mediates topotecan inhibition of Ube3a-antisense and allele-specific chromatin decondensation

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are oppositely imprinted autism-spectrum disorders with known genetic bases, but complex epigenetic mechanisms underlie their pathogenesis. The PWS/AS locus on 15q11-q13 is regulated by an imprinting control region that is maternally methylated ...

Divergent structural brain abnormalities between different genetic subtypes of children with Prader--Willi syndrome

Background Prader–Willi syndrome (PWS) is a complex neurogenetic disorder with symptoms that indicate not only hypothalamic, but also a global, central nervous system (CNS) dysfunction. However, little is known about developmental differences in brain structure in children with PWS. Thus, our aim wa...

Development of the Hypothalamic Melanocortin System

The melanocortin system is a critical component of the forebrain and hindbrain regulatory systems involved in energy balance. This system is composed of pro-opiomelanocortin (POMC) neurons that act, in part, through the melanocortin-4 receptor (MC4R). Although the importance of the melanocortin syst...

PYY3-36 and pancreatic polypeptide reduce food intake in an additive manner via distinct hypothalamic dependent pathways in mice

Objective: PYY3-36 and PP potently inhibit food intake in rodents and humans, however, it is unclear whether they have any synergistic/additive interaction in decreasing food intake. Design and Methods: Fasted WT, Y2-/- , Y4-/- or Y2Y4-/- mice were i.p. administrated with saline, PYY3-36 and/or PP. ...

An analysis of the topography, severity, potential sources of reinforcement, and treatments utilized for skin picking in Prader-Willi syndrome

We examined the topography, severity, potential sources of reinforcement, and treatments utilized for skin-picking behavior shown by individuals with Prader-Willi syndrome (PWS). The parents of 55 individuals with PWS, aged 6-25 years, were interviewed about their child's skin-picking behavior using...

A Prader-Willi locus lncRNA cloud modulates diurnal genes and energy expenditure

Prader-Willi syndrome (PWS), a genetic disorder of obesity, intellectual disability and sleep abnormalities, is caused by loss of noncoding RNAs on paternal chromosome 15q11-q13. The imprinted minimal PWS locus encompasses a long non-coding RNA (lncRNA) transcript processed into multiple SNORD116 sm...

Protein-binding elements established in the oocyte of primary imprint of the Prader-Willi/Angelman syndromes domain

Imprinting of the PWS/AS 2.4 Mb domain in the human is controlled by a paternally active imprinting center (PWS-IC). PWS-IC on the maternal allele is methylated and inactivated by an 880-bp sequence (AS-IC) located 30 kb upstream. In this communication, we report the identification of 7 cis acting e...

Case series of behavioral psychotherapy for obsessive-compulsive symptoms in youth with Prader-Willi syndrome

Obsessive-compulsive symptoms among youth with Prader-Willi Syndrome (PWS) are frequently present and associated with considerable problems in the daily functioning of the child and his/her family. Although pharmacological and psychosocial treatments exist that target obsessive-compulsive symptoms a...

Update on body composition and bone density in children with Prader-Willi Syndrome

Aim: To compare body composition in children with Prader-Willi syndrome (PWS) not naïve to growth hormone (GH) with obese and lean controls. Methods: Participants included 12 children with PWS, 12 children with obesity (body fat percentage >95th percentile for age and sex) and 12 lean children (b...

Pyrvinium pamoate changes alternative splicing of the serotonin receptor 2C by influencing its RNA structure

The serotonin receptor 2C plays a central role in mood and appetite control. It undergoes pre-mRNA editing as well as alternative splicing. The RNA editing suggests that the pre-mRNA forms a stable secondary structure in vivo. To identify substances that promote alternative exons inclusion, we set u...

Peptide inhibitors disrupt the serotonin 5-HT2C receptor interaction with phosphatase and tensin homolog to allosterically modulate cellular signaling and behavior

Serotonin (5-hydroxytryptamine; 5-HT) signaling through the 5-HT(2C) receptor (5-HT(2C)R) is essential in normal physiology, whereas aberrant 5-HT(2C)R function is thought to contribute to the pathogenesis of multiple neural disorders. The 5-HT(2C)R interacts with specific protein partners, but the ...

Imprinting in the CNS and neurodevelopment disorders

Genomic imprinting is allele-specific silencing based on maternal or paternal inheritance via epigenetic mechanisms. All imprinted loci express a long non-coding RNA (lncRNA) in an allele-specific manner dependent on a differentially methylated region (DMR). We describe the general mechanisms of gen...

R-loop formation is a distinctive characteristic of unmethylated human CpG island promoters

CpG islands (CGIs) function as promoters for approximately 60% of human genes. Most of these elements remain protected from CpG methylation, a prevalent epigenetic modification associated with transcriptional silencing. Here, we report that methylation-resistant CGI promoters are characterized by si...

Autonomic nervous system dysfunction in obesity and Prader–Willi syndrome: current evidence and implications for future obesity therapies

The autonomic nervous system (ANS) controls essential functions like breathing, heart rate, digestion, body temperature and hormone levels. Evidence suggests that ANS dysfunction is associated with adult and childhood obesity and plays a role in the distribution of total body fat and the development...

Temporal and developmental requirements for the Prader-Willi imprinting center

Imprinted gene expression associated with Prader-Willi syndrome (PWS) and Angelman syndrome (AS) is controlled by two imprinting centers (ICs), the PWS-IC and the AS-IC. The PWS-IC operates in cis to activate transcription of genes that are expressed exclusively from the paternal allele. We have cre...

A new deletion refines the boundaries of the murine Prader-Willi syndrome imprinting center

The human chromosomal 15q11-15q13 region is subject to both maternal and paternal genomic imprinting. Absence of paternal gene expression from this region results in Prader-Willi syndrome (PWS), while absence of maternal gene expression leads to Angelman syndrome. Transcription of paternally express...

Ghrelin mediates stress- induced food-reward behavior in mice

The popular media and personal anecdotes are rich with examples of stress-induced eating of calorically dense “comfort foods.” Such behavioral reactions likely contribute to the increased prevalence of obesity in humans experiencing chronic stress or atypical depression. However, the molecular subst...

Hypothalamic sites of leptin action linking metabolism and reproduction

A critical amount of energy reserve is necessary for puberty initiation, for normal sexual maturation and maintenance of cyclicity and fertility in females of most species. Therefore, the existence of circulating metabolic cues which directly modulate the hypothalamus-pituitary-gonad axis is predict...

Induced pluripotent stem cell models of the genomic imprinting disorders Angelman and Prader-Willi syndromes

Angelman syndrome (AS) and Prader–Willi syndrome (PWS) are neurodevelopmental disorders of genomic imprinting. AS results from loss of function of the ubiquitin protein ligase E3A (UBE3A) gene, whereas the genetic defect in PWS is unknown. Although induced pluripotent stem cells (iPSCs) provide inva...

A preliminary analysis of the phenomenology of skin-picking in Prader-Willi syndrome

To examine the nature and psychosocial correlates of skin-picking behavior in youth with Prader-Willi Syndrome (PWS). Parents of 67 youth (aged 5-19 years) with PWS were recruited to complete an internet-based survey that included measures of: skin-picking behaviors, the automatic and/or focused nat...

Neonatal maternal deprivation response and developmental changes in gene expression revealed by hypothalamic gene expression profiling in mice

Neonatal feeding problems are observed in several genetic diseases including Prader-Willi syndrome (PWS). Later in life, individuals with PWS develop hyperphagia and obesity due to lack of appetite control. We hypothesized that failure to thrive in infancy and later-onset hyperphagia are related and...

The snoRNA MBII-52 (SNORD 115) is processed into smaller RNAs and regulates alternative splicing

The loss of HBII-52 and related C/D box small nucleolar RNA (snoRNA) expression units have been implicated as a cause for the Prader–Willi syndrome (PWS). We recently found that the C/D box snoRNA HBII-52 changes the alternative splicing of the serotonin receptor 2C pre-mRNA, which is different from...

Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner

Background Ghrelin is a potent orexigenic hormone that likely impacts eating via several mechanisms. Here, we hypothesized that ghrelin can regulate extra-homeostatic, hedonic aspects of eating behavior. Methods In the current study, we assessed the effects of different pharmacological, physiologica...

PYY transgenic mice are protected against diet-induced and genetic obesity

The gut-derived hormone, peptide YY (PYY) reduces food intake and enhances satiety in both humans and animals. Obese individuals also have a deficiency in circulating peptide YY, although whether this is a cause or a consequence of obesity is unclear. Our aims were to determine whether peptide YY (P...

SnoRNA Snord116 (Pwcr1/MBII-85) deletion causes growth deficiency and hyperphagia in mice

Prader-Willi syndrome (PWS) is the leading genetic cause of obesity. After initial severe hypotonia, PWS children become hyperphagic and morbidly obese, if intake is not restricted. Short stature with abnormal growth hormone secretion, hypogonadism, cognitive impairment, anxiety and behavior problem...

The orexigenic hormone ghrelin defends against depressive symptoms in chronic stress

We found that increasing ghrelin levels, through subcutaneous injections or calorie restriction, produced anxiolytic- and antidepressant-like responses in the elevated plus maze and forced swim test. Moreover, chronic social defeat stress, a rodent model of depression, persistently increased ghrelin...

Loss of the Prader-Willi syndrome protein necdin causes defective migration, axonal outgrowth, and survival of embryonic sympathetic neurons

Prader-Willi syndrome is a neurodevelopmental disorder marked by abnormalities in feeding, drinking, thermoregulation, intestinal motility, and reproduction, suggesting disruption of the autonomic nervous system. Necdin, one of several proteins genetically inactivated in individuals with Prader-Will...

Genomic analysis of the chromosome 15q11-q13 Prader-Willi syndrome region and characterization of transcripts for GOLGA8E and WHCD1L1 from the proximal breakpoint region

Prader-Willi syndrome (PWS) is a neurobehavioral disorder characterized by neonatal hypotonia, childhood obesity, dysmorphic features, hypogonadism, mental retardation, and behavioral problems. Although PWS is most often caused by a paternal interstitial deletion of a 6-Mb region of chromosome 15q11...

Rapid generation of splicing reporters with pSpliceExpress

Almost all human protein-coding transcripts undergo pre-mRNA splicing and a majority of them is alternatively spliced. The most common technique used to analyze the regulation of an alternative exon is through reporter minigene constructs. However, their construction is time-consuming and is often c...

Pharmacological and molecular characterization of ATP-sensitive K+ conductances in CART and NPY/AgRP expressing neurons of the hypothalamic arcuate nucleus

The role of hypothalamic ATP-sensitive potassium channels in the maintenance of energy homeostasis has been extensively explored. However, how these channels are incorporated into the neuronal networks of the arcuate nucleus remains unclear. Whole-cell patch-clamp recordings from rat arcuate nucleus...

Integration of metabolic stimuli in the hypothalamic arcuate nucleus

Integration of peripheral and central anabolic and catabolic inputs within the hypothalamic arcuate nucleus (ARC) is believed to be central to the maintenance of energy balance. In order to perform this complex task, neurons in the ARC express receptors for all major humoral and central transmitters...

Peptide YY ablation in mice leads to the development of hyperinsulinaemia and obesity

AIMS/HYPOTHESIS: Obese people exhibit reduced circulating peptide YY (PYY) levels, but it is unclear whether this is a consequence or cause of obesity. We therefore investigated the effect of Pyy ablation on energy homeostasis. METHODS: Body composition, i.p. glucose tolerance, food intake and hypot...

Genetic mapping of putative Chrna7 and Luzp2 neuronal transcriptional enhancers due to impact of a transgene-insertion and 6.8 Mb deletion in a mouse model of Prader-Willi and Angelman syndromes.

BACKGROUND: Prader-Willi and Angelman syndrome (PWS and AS) patients typically have an approximately 5 Mb deletion of human chromosome 15q11-q13, of opposite parental origin. A mouse model of PWS and AS has a transgenic insertion-deletion (TgPWS/TgAS) of chromosome 7B/C subsequent to paternal or mat...

Lack of Pwcr1/MBII-85 snoRNA is critical for neonatal lethality in Prader-Willi syndrome mouse models.

Prader-Willi syndrome (PWS) is a neurobehavioral disorder caused by the lack of paternal expression of imprinted genes in the human chromosome region 15q11-13. Recent studies of rare human translocation patients narrowed the PWS critical genes to a 121-kb region containing PWCR1/HBII-85 and HBII-438...

Ghrelin, peptide YY and their receptors: gene expression in brain from subjects with and without Prader-Willi syndrome

Abstract Ghrelin and peptide YY (PYY) are peptides generally produced by the gastrointestinal organs which are involved in appetite regulation via highly specialized centers in the brain. Abnormal plasma ghrelin and PYY levels compared with controls have been reported for subjects with Prader-Willi ...

Hormonal and metabolic defects in a Prader-Willi syndrome mouse model with neonatal failure to thrive.

Prader-Willi syndrome (PWS) has a biphasic clinical phenotype with failure to thrive in the neonatal period followed by hyperphagia and severe obesity commencing in childhood among other endocrinological and neurobehavioral abnormalities. ! The syndrome results from loss of function of several clust...

Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus

The hypothalamic arcuate nucleus (ARC) integrates and responds to satiety and hunger signals and forms the origins of the central neural response to perturbations in energy balance. Here we show that rat ARC neurons containing neuropeptide Y (NPY) and agouti-related protein (AgRP), which are conditi...