Projects Archive - Foundation for Prader-Willi Research | Genetics and Imprinting

In year 1 of this project we found increased UBE3A levels in white blood cells was linked to more severe autism features, but only in non-deletion PWS (most matUPD). In year 2, we will analyze the dataset created in year 1 to help us understand how activity of UBE3A and other key genes (related to inflammatory and other dysregulated pathways)...

In this project we propose to use a newly-developed powerful tool to identify the specific nerve cells and genes that cause the hyperphagia in individuals with PWS and then screen for drugs to correct their functions and treat the obesity associated with PWS using the MAGEL2-null mouse model. We hypothesize that those cells showing significant...

In this project we propose to use a newly-developed powerful tool to identify the specific nerve cells and genes that cause the hyperphagia in individuals with PWS and then screen for drugs to correct their functions and treat the obesity associated with PWS using the MAGEL2-null mouse model. We hypothesize that those cells showing significant...

We expect that discovering the direct functions of snoRNAs will uncover new mechanisms – as well as revealing the fundamental basis of PWS. We propose to create a wide picture of RNA-RNA and RNA-protein interactions during the development of brain cells, focusing on interactions of SNORD116, as well as SNORD115 and other ncRNAs synthesized from...

Dr. Fon Tacer has been investigating the function of the MAGEL2 protein and believes it plays an important role in how cells adapt to stress. In this study she will explore how cellular stress responses are altered when MAGEL2 is lost.

The Snord116 gene is critical in PWS, but its normal function is incompletely understood. Dr. Good will establish an atlas of where and when the SNORD116 RNA is expressed in the developing mouse brain and how it interacts with one of its putative target genes, Nhlh2, to gain insight into the underlying molecular basis of PWS.

Dr. Derek Tai developed PWS cell lines representing type 1 and 2 deletions and has grown them as 3-D brain organoids, recapitulating the hypothalamus, in a dish. He has applied cutting edge technology to understand how PWS neurons differ from typical neurons and has generated data on gene expression changes. In year 2, he will expand the study to...

Differences in PWS symptoms across individuals may be due to variation in genes outside of the PWS critical region. To understand how genetic variants contribute to the severity and complexity of the disease, Dr. Bochukova will analyze variations in the genetic makeup of 160 PWS participants. With support from Soleno Therapeutics, biochemical,...

This study builds on the previous work of Dr. Godler, who developed a high throughput, economical test to detect chromosome 15 disorders in blood spots from newborns. Dr. Wheeler will transfer the technology to a newborn screening program in North Carolina to assess the feasibility of incorporating detection of chromosome 15 disorder into a...

Hyperphagia is thought to be a problem of neurons in the hypothalamus, caused by a dysregulation of neurons that signal being full and being hungry. Disruptions in the code for chemical modifications of RNA (called the epitranscriptome) can have detrimental effects on how neurons function. This project will use human hypothalamic hunger neurons...

Pancreatic beta cells produce and secrete two hormones, insulin and amylin, that are important regulators of food intake. These beta cells also express several PWS-region genes, but their function in the pancreas isn’t known. This project will shed light on the role of PWS genes in pancreatic beta cells by studying how PWS genes are regulated in...

Dr. Jo and his team are working on appetite-controlling pathways in the brain. Research has shown that mice lacking the Magel2 gene have fewer and less functional proopiomelanocortin (POMC) neurons, which are important in regulating appetite. These neurons appear to work through the amygdala, which is a part of the brain that is important in...

Dr. Tai and his team have used CRISPR genome editing techniques to generate a series of PWS deletion stem cells (small deletion, large deletion and single genes). Here, they will drive the cells to become hypothalamic neurons in a lab dish, then apply advanced technologies to study the cellular properties of these PWS neurons compared to typical...

 Dr. Resnick and his team have developed a mouse model of PWS that allows precise activation/replacement of the missing PWS genes at different times during development and in different tissues. In this second year of funding, they will work to reestablish gene expression and determine the effects on the potential reversal of traits. This study...

SNORD116 is a C/D box small nucleolar RNA that is critical for the etiology of PWS, as microdeletions encompassing only SNORD116 cause a PWS-like phenotype. The molecular functions of SNORD116 have been elusive, preventing therapy design. We showed that SNORD116 is not a typical snoRNA, as it associates with different proteins and has a different...

Prader-Willi syndrome (PWS) traits are genetically determined by the loss of expression of genes from the paternally inherited small region located on chromosome 15. These genes are transcribed to brain-specific small nucleolar RNAs (snoRNAs) whose function is still unknown. snoRNAs were traditionally assigned a role in ribosomal RNA processing...

The role of the brain in controlling food intake is increasingly apparent, with studies finding that genes related to obesity often play a role in brain regions crucial for feeding, appetite, and satiety. Prader-Willi syndrome, one of the most common forms of genetic obesity, results increased food intake (hyperphagia) leading to severe obesity,...

Deletions on chromosome 15 in the bands labeled 15q11.2-q13 on the chromosome inherited from a subject’s father cause Prader-Willi syndrome (PWS). The unique nature of this causative genetic event has been known for many years, but the precise manner in which it causes the developmental abnormalities of PWS is not completely understood since the...

Prader-Willi Syndrome (PWS) is a genetic condition resulting from paternal inheritance of a deletion within an imprinted region of chromosome 15q. The smallest known deleted region encompasses a small nucleolar non-coding RNA locus called SNORD116 (SNORD116), but very little is known about how deletion of SNORD116 leads to PWS. As shown using...

Recent studies with oxytocin treatment in PWS have yielded inconsistent results. Intranasal administration of oxytocin by the Toulouse group decreased disruptive behaviors in patients with PWS, but a recent randomized trial in Australia of adolescents and adults of intranasal oxytocin (IN-OT) found no effect on syndrome-specific behavior in...

There are two goals to this study: 1) To identify differences between individuals with PWS with autism from those who have PWS without autism using technology that analyzes how genes are expressed and 2) To identify a new role for SNORD115 and SNORD116 which may help explain the PWS condition or how other very small molecules that do not make...

Prader-Willi syndrome (PWS) is a severe neurodevelopmental disorder found in ~1 in 15,000 to 20,000 births. PWS phenotype caused by the loss of function of several genes located on chromosome 15. These genes are usually ‘switched on’ on the chromosome 15 that is inherited from the father and ‘switched off’ on the chromosome 15 inherited from the...

Although it is well established that deletion of SNORD116 contributes to PWS in humans, mice missing Snord116 don’t display hyperphagia and obesity. This makes it very difficult to study the biology of SNORD116 and test anti-obesity drugs. In a major breakthrough, Dr. Yeo’s group has shown that if Snord116 is deleted in adult mice, a percentage of...

The loss of two snoRNAs, SNORD115 and SNORD116, plays a central role in the development of Prader-Willi syndrome. However, the normal function of SNORD116 is still unclear, making it difficult to understand what goes wrong when SNORD116 is lost. Dr. Stamm’s group is exploring how SNORD116 influences other genes, and their preliminary studies...

Despite the significant progress in understanding the molecular basis underlying Prader-Willi syndrome, little advance has been achieved in developing the treatment specifically targeting to the molecular defect. The SNORD116 between the SNRPN and UBE3A genes is important for the major features of PWS. The host transcripts and SNORD116 in the...

Through a normal biological process called genomic imprinting, the chromosome 15 that is inherited from the father has a set of genes that are switched on while the same set of genes on the chromosome 15 inherited from the mother are switched off. In Prader-Willi syndrome (PWS), there is no normal copy of the paternal chromosome 15 so patients...

A hallmark symptom of PWS is extreme, unrelenting hyperphagia associated with obesity. Other medical characteristics of individuals with PWS include low circulating growth hormone, short stature, adrenal insufficiency, hypothyroidism, and hypogonadism. Additionally, individuals with PWS have decreased levels of circulating fasting insulin compared...

The genetic causes of Prader-Willi syndrome (PWS) are known, including as a complex disorder involving imprinted genes that normally only function after inheritance from the father. A dozen genes contribute to the clinical problems in PWS, although what most of these genes do is poorly understood. Additionally, although numerous mouse models that...

Current evidence suggests that most Prader-Willi syndrome (PWS) traits result from loss of paternally inherited SNORD116 gene group. SNORD116 belong to a class of small nucleolar RNAs (snoRNAs), which are involved in modification of other RNA species. snoRNAs act as guides to define sites of target RNA modification by partner enzymes. Typically, a...

There are two goals to this study: 1) To identify differences among individuals with PWS and autism from those who have PWS without autism by analyzing gene expression and 2) To identify new patterns of gene expression which may help explain the PWS condition or how other very small molecules that do not make protein (non-coding RNAs) implicated...

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder with a known genetic etiology, but a complex epigenetic basis.  PWS is an imprinted disorder, meaning that the genes implicated in PWS are expressed only on the paternal but not the maternal chromosome 15q11-13. At the heart of the minimally deleted region in PWS are several processed...

For several decades the most extensively studied human DNA sequences were those generating messenger RNAs (mRNAs) which are used as templates for protein synthesis. The process decoding the genetic information from mRNAs to proteins is carried out by molecular machines named ribosomes and proteins are commonly perceived as essential molecules...

Through a normal biological process called genomic imprinting, the chromosome 15 that is inherited from the father has a set of genes that are switched on while the same set of genes on the chromosome 15 inherited from the mother are switched off. In Prader-Willi syndrome (PWS), there is no normal copy of the paternal chromosome 15 so patients...

A publication resulting from this project 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 caused by a loss of genes normally expressed only from the paternal chromosome 15. About 70% of PWS cases arise from Type 1 and Type 2 deletions, which are about 5 million DNA base pairs in size. Genetic mapping data from unique patients harboring smaller deletions, “microdeletions”, in the PWS region implicate the...

Prader-Willi syndrome (PWS) is a rare genomic imprinting disorder caused by an abnormality in the PWS critical region (PWSCR), a particular region of 15th chromosome (15q11-q13). Genomic imprinting refers to a phenomenon in which genes from specific parent can be expressed. PWSCR contains several imprinted genes that are only expressed from either...

This proposal will investigate the development of a gene therapy for Prader-Willi syndrome (PWS). PWS is caused by the loss of a region of human chromosome 15q11-13. Humans have two copies of chromosome 15, one the mother (maternal) and one from the father (paternal). Due to an unusual mechanism called genetic imprinting, the genes affecting PWS...

Prader-Willi syndrome (PWS) is caused by a loss of genes normally expressed only from the paternal chromosome 15. About 70% of PWS cases arise from Type 1 and Type 2 deletions, which are about 5 million DNA base pairs in size. Genetic mapping data from unique patients harboring smaller deletions, “microdeletions”, in the PWS region implicate the...

Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder, predominantly caused by a deletion on the long arm of chromosome 15. This deletion eliminates a group of genes called HBII-85 whose function is currently unknown. Therefore, this proposal aims to investigate the underlaying molecular mechanisms behind the loss of HBII-85 and how this...

Prader-Willi Syndrome (PWS), a complex genetic disorder that results from a failure to inherit a normal copy of the father’s chromosome 15. Key genes on the paternal chromosome are deleted, but how the deletion of this region leads to PWS is a complete mystery. In PWS, a normal copy of the mother’s chromosome 15 is inherited, but the genes are...

This proposal will investigate the development of a gene therapy for Prader-Willi syndrome (PWS). PWS is caused by the loss of a region of human cromosome 15q11-13. Humans have two copies of chromosome 15, one the mother (maternal) and one from the father (paternal). Due to an unusual mechanism called genetic imprinting, the genes affecting PWS...

Like most genetic disorders, there is no specific therapeutic intervention targeted to the molecular defect for Prader-Willi syndrome (PWS). The clinical presentations of PWS are caused by paternal deficiency of genes in the chromosome 15q11-q13 region. Recent reports indicate a region between the SNRPN and UBE3A genes harboring SnoRNA clusters is...

Although the genetic region on chromosome 15 that is responsible for Prader-Willi Syndrome (PWS) has been known for many years, how the gene or genes within this large region cause the complex clinical features of PWS is still unknown. We have identified a small deletion on chromosome 15 of a patient with PWS features that narrows the causative...

Two lines of evidence are promoted this proposal. First, recently, smaller microdeletions in the region between the human SNRPN and UBE3A genes have been reported in several cases with features consistent with PWS, including childhood obesity, hyperphagia, and hypogonadism. Second, interestingly, recent studies of genomewide survey of imprinting...

The overall goals of our research are to elucidate the pathophysiologic pathways that lead to the metabolic and behavioral changes in PWS, and to evaluate two types of treatments for persistent hunger and food seeking behavior. We have focused on the role of a special type of RNA, called Snord116 (formally PWCR1/HBII-85) small nucleolar RNA...

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder with a known genetic etiology but a complex epigenetic basis. PWS is an imprinted disorder, meaning that genes expressed only on the paternal but not the maternal chromosome 15 are responsible. Furthermore, unlike genetic mutations that affect protein-coding genes, the smallest genetic...

A better understanding of the causes of Prader-Willi syndrome (PWS) and the discovery of potential therapies has been hampered by the unavailability of live tissues. In our laboratory (Marc Lalande), we have established induced pluripotent stem cell (iPSC) technology to create models of human disease in a test tube/tissue culture dish. Skin cells...

Genetic studies strongly indicate that the Prader-Willi syndrome is caused by the loss of small nucleolar RNAs (snoRNA). SnoRNAs are short RNAs that do not encode a protein. In most cases studied, snoRNAs help in the modification of other RNAs. However, the function of the snoRNAs missing in people with Prader-Willi syndrome is not clear. In...

It has been known for many years that loss of function of the copy of the DNA inherited from the father for genes in the Prader-Willi syndrome (PWS) region cause PWS. However, there are multiple genes in the region, and it has not been clear as to exactly which gene or genes cause PWS. Based on studies of a series of rare families with...

At the genetic level, Prader-Willi syndrome (PWS) is due to the lack of expression of a specific portion of chromosome 15. This portion contains genes that, in normal circumstances, are only active on the paternally inherited chromosome. Indeed, the corresponding genes on the maternally inherited chromosome are silenced – a phenomenon called...

The cause of the severe obesity characteristic of patients with Prader-Willi syndrome (PWS) is unknown. In the past few years however, there has been an explosion of information regarding the factors involved in the control of bodyweight. In particular, the hormone leptin, which is produced by fat, and a group of molecules in the brain called the...

Prader Willi syndrome is caused by the loss of gene expression from a known region in the human genome. In almost all genetic diseases studied, the loss of gene expression results in a loss of a certain protein, since ultimately proteins are made from genes. One problem in understanding the Prader-Willi syndrome is that only a few proteins are...

The overall goals of our research are to elucidate the genetic and pathophysiologic pathways that lead to the metabolic and behavioral changes in PWS. We have focused on the role of a special type of RNA, called PWCR1/HBII85 small nucleolar RNA (snoRNA), that was discovered in our laboratory. Studies of rare cases of PWS with smaller deletions and...

The overall goals of our research are to elucidate the genetic and pathophysiologic pathways that lead to the metabolic and behavioral changes in PWS. We believe that a detailed level of understanding is necessary to design rational interventions. Recently, our laboratory has focused on the role of a special type of RNA, called PWCR1/HBII-85 small...

More than 95% of Prader-Willi syndrome (PWS) cases are caused by either a large deletion of paternal chromosome 15q11-q13 or maternal uniparental disomy (UPD) of chromosome 15. The major gene or genes responsible for PWS are subject to genomic imprinting and exclusively expressed from paternal chromosome. For patients with a large chromosomal...

Prader-Willi syndrome (PWS) results from inactivation of a domain on the paternal chromosome 15 while the same domain on chromosome 15 that is of maternal origin is normally inactivated. This situation in Prader-Willi patients is therefore associated with complete silencing of a relatively large number of genes that are located in this domain....

At the genetic level, Prader-Willi syndrome (PWS) is due to the lack of expression of a specific portion of chromosome 15. This portion contains genes that, in normal circumstances, are only active on the paternally inherited chromosome. Indeed, the corresponding genes on the maternally inherited chromosome are silenced – a phenomenon called...

Prader-Willi syndrome (PWS) results from inactivation of a domain on the paternal chromosome 15 while the same domain on chromosome 15 that is of maternal origin is normally inactivated. This situation in Prader-Willi patients is therefore associated with complete silencing of a relatively large number of genes that are located in this domain....