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Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2
- Source :
- Journal of Medical Genetics. 60:406-415
- Publication Year :
- 2022
- Publisher :
- BMJ, 2022.
-
Abstract
- BackgroundSchaaf-Yang syndrome (SYS) is caused by truncating mutations inMAGEL2, mapping to the Prader-Willi region (15q11-q13), with an observed phenotype partially overlapping that of Prader-Willi syndrome. MAGEL2 plays a role in retrograde transport and protein recycling regulation. Our aim is to contribute to the characterisation of SYS pathophysiology at clinical, genetic and molecular levels.MethodsWe performed an extensive phenotypic and mutational revision of previously reported patients with SYS. We analysed the secretion levels of amyloid-β 1–40 peptide (Aβ1-40) and performed targeted metabolomic and transcriptomic profiles in fibroblasts of patients with SYS (n=7) compared with controls (n=11). We also transfected cell lines with vectors encoding wild-type (WT) or mutated MAGEL2 to assess stability and subcellular localisation of the truncated protein.ResultsFunctional studies show significantly decreased levels of secreted Aβ1-40and intracellular glutamine in SYS fibroblasts compared with WT. We also identified 132 differentially expressed genes, including non-coding RNAs (ncRNAs) such asHOTAIR, and many of them related to developmental processes and mitotic mechanisms. The truncated form of MAGEL2 displayed a stability similar to the WT but it was significantly switched to the nucleus, compared with a mainly cytoplasmic distribution of the WT MAGEL2. Based on the updated knowledge, we offer guidelines for the clinical management of patients with SYS.ConclusionA truncated MAGEL2 protein is stable and localises mainly in the nucleus, where it might exert a pathogenic neomorphic effect. Aβ1-40secretion levels andHOTAIRmRNA levels might be promising biomarkers for SYS. Our findings may improve SYS understanding and clinical management.
- Subjects :
- nervous system diseases
Síndromes
Trastorns del metabolisme
Syndromes
Proteins
Errors congènits del metabolisme
Inborn errors of metabolism
Síndrome de Prader-Willi
Phenotype
Disorders of metabolism
disease management
Mutation
central nervous system diseases
gene expression
Genetics
Humans
Prader-Willi syndrome
clinical genetics
Biomarkers
Genetics (clinical)
Subjects
Details
- ISSN :
- 14686244 and 00222593
- Volume :
- 60
- Database :
- OpenAIRE
- Journal :
- Journal of Medical Genetics
- Accession number :
- edsair.doi.dedup.....e24d5e784d6c07edc91aacacec732b52