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

Autor:	Castilla-Vallmanya L; Department of Genetics, Microbiology and Statistics, IBUB, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.; Institut de Recerca Sant Joan de Déu, Espluques de Llobregat, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instiuto de Salud Carlos III, Madrid, Spain., Centeno-Pla M; Department of Genetics, Microbiology and Statistics, IBUB, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.; Institut de Recerca Sant Joan de Déu, Espluques de Llobregat, Barcelona, Spain.; Clinical Biochemistry Department, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain., Serrano M; Institut de Recerca Sant Joan de Déu, Espluques de Llobregat, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instiuto de Salud Carlos III, Madrid, Spain.; Neurology Department, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain., Franco-Valls H; Department of Genetics, Microbiology and Statistics, IBUB, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain., Martínez-Cabrera R; Department of Genetics, Microbiology and Statistics, IBUB, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain., Prat-Planas A; Department of Genetics, Microbiology and Statistics, IBUB, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.; Institut de Recerca Sant Joan de Déu, Espluques de Llobregat, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instiuto de Salud Carlos III, Madrid, Spain., Rojano E; Department of Molecular Biology and Biochemistry; Institute of Biomedical Research in Málaga (IBIMA), University of Málaga, Málaga, Spain., Ranea JAG; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instiuto de Salud Carlos III, Madrid, Spain.; Department of Molecular Biology and Biochemistry; Institute of Biomedical Research in Málaga (IBIMA), University of Málaga, Málaga, Spain., Seoane P; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instiuto de Salud Carlos III, Madrid, Spain.; Department of Molecular Biology and Biochemistry; Institute of Biomedical Research in Málaga (IBIMA), University of Málaga, Málaga, Spain., Oliva C; Institut de Recerca Sant Joan de Déu, Espluques de Llobregat, Barcelona, Spain.; Clinical Biochemistry Department, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain., Paredes-Fuentes AJ; Institut de Recerca Sant Joan de Déu, Espluques de Llobregat, Barcelona, Spain.; Clinical Biochemistry Department, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain., Marfany G; Department of Genetics, Microbiology and Statistics, IBUB, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.; Institut de Recerca Sant Joan de Déu, Espluques de Llobregat, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instiuto de Salud Carlos III, Madrid, Spain., Artuch R; Institut de Recerca Sant Joan de Déu, Espluques de Llobregat, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instiuto de Salud Carlos III, Madrid, Spain.; Clinical Biochemistry Department, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain., Grinberg D; Department of Genetics, Microbiology and Statistics, IBUB, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.; Institut de Recerca Sant Joan de Déu, Espluques de Llobregat, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instiuto de Salud Carlos III, Madrid, Spain., Rabionet R; Department of Genetics, Microbiology and Statistics, IBUB, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.; Institut de Recerca Sant Joan de Déu, Espluques de Llobregat, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instiuto de Salud Carlos III, Madrid, Spain., Balcells S; Department of Genetics, Microbiology and Statistics, IBUB, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.; Institut de Recerca Sant Joan de Déu, Espluques de Llobregat, Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instiuto de Salud Carlos III, Madrid, Spain., Urreizti R; Institut de Recerca Sant Joan de Déu, Espluques de Llobregat, Barcelona, Spain roserurreizti@gmail.com.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instiuto de Salud Carlos III, Madrid, Spain.; Clinical Biochemistry Department, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain.
Jazyk:	angličtina
Zdroj:	Journal of medical genetics [J Med Genet] 2023 Apr; Vol. 60 (4), pp. 406-415. Date of Electronic Publication: 2022 Sep 07.
DOI:	10.1136/jmg-2022-108690
Abstrakt:	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 (Aβ 1-40 ) 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 Aβ 1-40 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. Aβ 1-40 secretion levels and HOTAIR mRNA levels might be promising biomarkers for SYS. Our findings may improve SYS understanding and clinical management. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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