Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2

Abstract

BackgroundSchaaf-Yang syndrome (SYS) is caused by truncating mutations in MAGEL2, 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 Aβ1-40 and intracellular glutamine in SYS fibroblasts compared with WT. We also identified 132 differentially expressed genes, including non-coding RNAs (ncRNAs) such as HOTAIR, 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. Aβ1-40 secretion levels and HOTAIR mRNA levels might be promising biomarkers for SYS. Our findings may improve SYS understanding and clinical management.

Hao-Fountain Syndrome: 32 novel patients reveal new insights into the clinical spectrum

“…Patients presented with developmental delay (DD), autism spectrum disorder (ASD), seizures, a behavioral phenotype, and signs of hypogonadism. Intriguingly, this clinical presentation shows great overlap with PWS and SYS by neurodevelopmental delay, failure to thrive, endocrine disruptions, behavioral anomalies, and muscular hypotonia 5,7–9 .…”

Hao‐Fountain syndrome: 32 novel patients reveal new insights into the clinical spectrum

“…Patients presented with developmental delay (DD), autism spectrum disorder (ASD), seizures, a behavioral phenotype, and signs of hypogonadism. Intriguingly, this clinical presentation shows great overlap with PWS and SYS by neurodevelopmental delay, failure to thrive, endocrine disruptions, behavioral anomalies, and muscular hypotonia 5,7–9 …”

“…Intriguingly, this clinical presentation shows great overlap with PWS and SYS by neurodevelopmental delay, failure to thrive, endocrine disruptions, behavioral anomalies, and muscular hypotonia. 5,[7][8][9] To date, the largest cohort of patients affected by Hao-Fountain Syndrome (HAFOUS, OMIM: #616863) was presented by Fountain et al in 2019 describing 16 novel patients. 6 The consistency of symptoms, regardless of the underlying variant type, supported the concept of USP7 haploinsufficiency as the causal factor of the disorder.…”

Subcellular localization of truncated MAGEL2 proteins: insight into the molecular pathology of Schaaf-Yang syndrome

“…In a previous study, to characterize the functional consequences of MAGEL2 truncation, we transfected vectors encoding hemagglutinin (HA)-tagged wild-type (WT) or one particular truncated MAGEL2 (MAGEL2-Gln638*) and assessed their subcellular localization (10).…”