Schaaf Research Connects Missing MAGEL2 Gene to PWS Symptoms

schaaf-research-connects-missing-magel2-gene-to-pws-symptoms.jpgPrader Willi syndrome (PWS) results when a set of key genes on chromosome 15 are missing and/or inactive. Figuring out the role played by each of these genes in PWS is a major goal for PWS research. One of the genes in the PWS region is called MAGEL2.

Dr. Christian Schaaf is actively pursuing the question of how a missing — or disrupted — MAGEL2 gene translates into the classic symptoms of PWS and related genetic disorders. He's particularly interested in testing the connection between MAGEL2 and autism-like behaviors.

Dr. Schaaf's work has been supported by FPWR in two funding cycles. I recently talked with him about his background, research, and focus on PWS.

Early Work: Solving Medical Mysteries, Helping Families

Dr. Schaaf’s interest in medicine extends back to high school in Germany, and a yearlong class in human biology.  Subsequently, to fulfill his German civilian service immediately after high school, Dr. Schaaf worked for the Red Cross for 15 months in emergency medical training, truly enjoying the experience. In medical school at the University of Heidelberg, he realized his love for pediatric medicine, and in solving medical mysteries, investigating cases where others hadn’t found the answers as to what was wrong. He witnessed the frustration and anxiety of parents not knowing why their children were ill, and the satisfaction in figuring out the causes of mystery illnesses, leading to effective treatments.

Medical School: Combining Clinical with Research

During medical school, Dr.Schaaf did research in a lab focusing on cancer genetics, and obtained a combined MD and PhD degree. He also had a unique opportunity, through a scholarship from the Foundation for German Business, to travel to and train in New York, Toronto, and Tasmania. During his final year of medical training, Dr. Schaaf did a 4 month rotation at Baylor College of Medicine in Houston, engaging in a mixture of clinical and research work. Here, he deeply appreciated the fact that the department was equally strong in both clinical and research approaches, that there was significant collaboration within the department, and a direct translation between basic research and clinical applications (i.e., both “bench” and “bedside” work).

At the end of 4 months, he was hooked on Baylor, and decided to do his medical residency there. Dr. Schaaf was a resident at Baylor from 2006-2010, after which he became an assistant professor (tenure-track since 2013). He currently holds the title of Assistant Professor of Molecular and Human Genetics at Baylor, and his lab is located at the Neurological Research Institute of Texas Children’s Hospital, where he is an Investigator.  He is also the Chair of the Education Committee of the American College of Medical Genetics and has written a textbook for human genetics, Human Genetics: From Molecules to Medicine.

Current Work With Genetic Disorders

Research in Dr. Schaaf’s lab is devoted to understanding the genetics of neurodevelopmental and neuropsychological disorders including those related to autism. Dr. Schaaf uses mouse models to pursue these questions, as well as generating stem cells with particular genetic profiles (i.e., deletions, mutations), which can then be programmed to become a particular type of cell. He and his research group also collect data directly from patients affected by genetic disorders. There are a few genes in particular whose role in neurodevelopmental disorders Dr. Schaaf is currently studying. These include the genes, CHRNA7, NR2F1, and MAGEL2.

Dr. Schaaf’s study of the MAGEL2 gene is extremely important for advancing our understanding of the genetic basis of PWS and related disorders. He came to MAGEL2 research almost by chance when a patient was referred to him with an indication of autism spectrum disorder (given Dr. Schaaf’s longstanding interest in autism genetics). Furthermore, the patient showed some of the symptoms of PWS, but standard genetic testing for PWS was negative. The patient was then revealed to have a so-called truncating point mutation” in the MAGEL2 gene. A point mutation consists of a substitution, insertion, or deletion of a single base pair.

In the case of a truncating point mutation for a protein-coding gene like MAGEL2 (which leads to the synthesis of a protein when functioning normally), the mutation disrupts — or truncates — the process of protein coding, i.e., the very function of the gene. Dr. Schaaf then found 3 more cases of patients with similar truncating point mutations in MAGEL2, with very similar associated “PWS-like” clinical symptoms. However, there are some important differences with respect to PWS that are associated with the MAGEL2 point mutation, including problems with joint contracture (tightening), and a much higher rate of autism spectrum disorder.

These distinctions eventually led to the disorder arising from MAGEL2 point mutation receiving a separate title; it is now called Schaaf-Yang syndrome, after Dr. Schaaf and Dr. Yaping Yang, who directs the Whole Genome Laboratory at Baylor (whose database was crucial for identifying additional cases of MAGEL2 point mutations).

Role of MAGEL2 In PWS Symptoms

Dr. Schaaf and his lab are currently considering the question of MAGEL2 and PWS from multiple different angles. With support from FPWR, they are using genetically altered mice lacking the MAGEL2 gene, systematically evaluating the behavior patterns of such mice in direct comparison with those of genetically normal mice, and searching for signs of autism-like patterns in the MAGEL2-deletion mice. They are also conducting a comparative study of the behavioral, cognitive, and hormonal profiles of 10 human patients with point mutations in MAGEL2, along with those of individuals with classical PWS. This comparison will highlight the specific role of MAGEL2 in the symptoms of PWS — just as studies of patients with microdeletions of the SNORD116 gene alone demonstrated the importance of that gene in the manifestation of hyperphagia.

One important discovery is that MAGEL2 mice appear to be deficient in oxytocin, a hormone whose deficiency in individuals with PWS has been linked to a wide range of behavior problems. Disruption in the expression of MAGEL2 may lead at least in part to oxytocin problems in PWS. Dr. Schaaf is therefore extremely optimistic about ongoing and planned oxytocin trials for the PWS community, and sees oxytocin treatment — especially during infancy — as a key component of treating the behavioral challenges associated with PWS.

FPWR has had an important impact on Dr. Schaaf’s research, providing not only financial support, but connecting him with other top researchers in the field of PWS research such as Dr. Rachel Wevrick, Dr. Maithe Tauber, Dr. Jennifer Miller, Dr. Marc LaLande, Dr. Francoise Muscatelli and Dr. Rudy Leibel, some of whom he met at FPWR's research conference.

Outside the lab, Dr. Schaaf and his wife keep very busy with their family of three (soon to be four) children, all of whom are 5 years old and under. Dr. Schaaf enjoys the outdoors, including hiking and skiing in the mountains, which he misses, living in Houston. He also enjoys riding his bike to work every day.

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Topics: Research

Alice Shapley

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Alice, mother to Anna, interviews PWS researchers for the FPWR Researcher Spotlight section of the website and the FPWR blog. She has also served as a parent advocate grant reviewer for FPWR since 2014, and has fundraised for One Small Step walks since 2013. Alice is a professor of astronomy at UCLA and enjoys using her science background to connect PWS researchers and other parents. She lives in Los Angeles with her husband, Edwin, also a professor at UCLA, and their two beautiful children, Anna and Jacob.

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