Funding Summary
Studies using cell and animal models are needed to better understand the normal function of MAGEL2 and how mutations or loss of the protein underlies both the PWS and SYS phenotypes. This funded project will support a postdoctoral fellow in Dr. Christian Schaaf’s lab to investigate the molecular biology of MAGEL2 in both PWS and SYS. This will include developing a functional and robust assay MAGEL2 function to assess the consequences of mutations and provide a system for evaluating potential therapeutic approaches, as well as understand the epigenetics and transcriptional control of this region. This funding will support a postdoctoral fellow in Dr. Christian Schaaf’s lab for 3 years, focused entirely on investigating the molecular biology of MAGEL2 in both PWS and SYS.
Dr. Theresa Strong, Director of Research Programs, explains the details of the project in this video clip.
Lay Abstract
Schaaf-Yang syndrome [SYS, OMIM #615547], first identified in 2013, is a rare genetic disorder affecting multiple systems. SYS is caused by mutations in the maternally imprinted, paternally expressed MAGEL2 gene, located in the Prader-Willi syndrome (PWS) region of chromosome 15q11-13 [NCBI Gene ID: 54551]. To date, all reported mutations are predicted to result in a truncated protein. Many clinical features of SYS overlap with PWS, including profound neonatal hypotonia, feeding difficulties, developmental delay/intellectual disability, behavioral problems and endocrine abnormalities. However, additional features are more common in SYS than in PWS, such as contractures, autism and severe intellectual disability. The full phenotypic spectrum of SYS remains to be defined, and the natural history of the disorder is incompletely characterized. Further, while cellular studies have identified a role for the MAGEL2 protein in membrane protein recycling and endosomal sorting through facilitation of the retromer recycling pathway, questions remain about the normal function of this protein and how disruption of its cellular function contributes to disease.
Studies using cell and animal model are needed to better understand the normal function of MAGEL2 and how mutations or loss of the protein underlies both the PWS and SYS phenotypes. The epigenetics/transcriptional control of the region is incompletely understood. In addition, studies are needed to definitively determine if SYS is caused by loss of function or if a gain of function is associated with some mutations. To this end, it remains to be determined if a truncated protein or protein with an alternative C-terminal end (frameshift) is produced in some SYS patients. A robust assay for MAGEL2 function is needed to assess the consequences of mutations and provide a system for evaluating potential therapeutic approaches.
Funded Year:
2023
Awarded to:
Christian Schaaf, MD, PhD
Amount:
$370,980
Institution:
University of Heidelberg
Researcher:
Christian Schaaf, MD, PhD
