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Title: Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2
Author: Castilla-Vallmanya, Laura
Centeno-Pla, Mónica
Serrano, Mercedes
Franco-Valls, Héctor
Martínez-Cabrera, Raúl
Prat-Planas, Aina
Rojano, Elena
Ranea, Juan A G
Seoane, Pedro
Oliva, Clara
Paredes-Fuentes, Abraham J
Marfany i Nadal, Gemma
Artuch, Rafael
Grinberg Vaisman, Daniel Raúl
Rabionet Janssen, Raquel
Balcells Comas, Susana
Urreizti, Roser
Keywords: Síndrome de Prader-Willi
Errors congènits del metabolisme
Trastorns del metabolisme
Prader-Willi syndrome
Inborn errors of metabolism
Disorders of metabolism
Issue Date: 7-Sep-2022
Publisher: BMJ Publishing Group
Abstract: 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.
Note: Versió postprint del document publicat a:
It is part of: Journal of Medical Genetics, 2022
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ISSN: 0022-2593
Appears in Collections:Articles publicats en revistes (Genètica, Microbiologia i Estadística)

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