RT Journal Article
SR Electronic
T1 Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 406
OP 415
DO 10.1136/jmg-2022-108690
VO 60
IS 4
A1 Laura Castilla-Vallmanya
A1 Mónica Centeno-Pla
A1 Mercedes Serrano
A1 Héctor Franco-Valls
A1 Raúl Martínez-Cabrera
A1 Aina Prat-Planas
A1 Elena Rojano
A1 Juan A G Ranea
A1 Pedro Seoane
A1 Clara Oliva
A1 Abraham J Paredes-Fuentes
A1 Gemma Marfany
A1 Rafael Artuch
A1 Daniel Grinberg
A1 Raquel Rabionet
A1 Susanna Balcells
A1 Roser Urreizti
YR 2023
UL http://jmg.bmj.com/content/60/4/406.abstract
AB Background Schaaf-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.Methods We 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.Results Functional 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.Conclusion A 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.Data are available on reasonable request.