RT Journal Article
T1 Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2.
A1 Castilla-Vallmanya, Laura
A1 Centeno-Pla, Mónica
A1 Serrano, Mercedes
A1 Franco-Valls, Héctor
A1 Martínez-Cabrera, Raúl
A1 Prat-Planas, Aina
A1 Rojano, Elena
A1 Ranea, Juan A G
A1 Seoane, Pedro
A1 Oliva, Clara
A1 Paredes-Fuentes, Abraham J
A1 Marfany, Gemma
A1 Artuch, Rafael
A1 Grinberg, Daniel
A1 Rabionet, Raquel
A1 Balcells, Susanna
A1 Urreizti, Roser
K1 central nervous system diseases
K1 clinical genetics
K1 disease management
K1 gene expression
K1 nervous system diseases
AB 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. 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. 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. 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.
YR 2022
FD 2022-09-07
LK http://hdl.handle.net/10668/20161
UL http://hdl.handle.net/10668/20161
LA en
DS RISalud
RD Apr 9, 2025