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Subcellular localisation of truncated MAGEL2 proteins: insight into the molecular pathology of Schaaf-Yang syndrome
  1. Mónica Centeno-Pla1,2,
  2. Estefanía Alcaide-Consuegra1,2,
  3. Sophie Gibson1,
  4. Aina Prat-Planas1,2,
  5. Juan Diego Gutiérrez-Ávila1,2,
  6. Daniel Grinberg1,2,
  7. Roser Urreizti2,3,
  8. Raquel Rabionet1,2,
  9. Susanna Balcells1,2
  1. 1Department of Genetics, Microbiology and Statistics, Facultat de Biologia, IBUB, IRSJD, Universitat de Barcelona, Barcelona, Catalunya, Spain
  2. 2Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
  3. 3Clinical Biochemistry Department, IRSJD, Hospital Sant Joan de Déu, Esplugues de Llobregat, Catalunya, Spain
  1. Correspondence to Dr Susanna Balcells, Department of Genetics, Microbiology and Statistics, IBUB, IRSJD, Universitat de Barcelona Facultat de Biologia, Barcelona, Catalunya 08028, Spain; sbalcells{at}


Schaaf-Yang syndrome (SYS) is an ultra-rare neurodevelopmental disorder caused by truncating mutations in MAGEL2. Heterologous expression of wild-type (WT) or a truncated (p.Gln638*) C-terminal HA-tagged MAGEL2 revealed a shift from a primarily cytoplasmic to a more nuclear localisation for the truncated protein variant. We now extend this analysis to six additional SYS mutations on a N-terminal FLAG-tagged MAGEL2. Our results replicate and extend our previous findings, showing that all the truncated MAGEL2 proteins consistently display a predominant nuclear localisation, irrespective of the C-terminal or N-terminal position and the chemistry of the tag. The variants associated with arthrogryposis multiplex congenita display a more pronounced nuclear retention phenotype, suggesting a correlation between clinical severity and the degree of nuclear mislocalisation. These results point to a neomorphic effect of truncated MAGEL2, which might contribute to the pathogenesis of SYS.

  • Clinical genetics
  • Nervous System Diseases
  • Gain of Function Mutation
  • Mutation

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  • RR and SB contributed equally.

  • Contributors RU, EA-C, AP-P and MC-P designed the cloning strategy. EA-C, MC-P and SG participated in the cloning of the plasmids. MC-P and SG conducted the cell culture, transfection and immunofluorescence staining experiments. MC-P and JDG-A analysed the ICC assays. MC-P and EA-C elaborated the corresponding figures and tables. SB, DG, RR and RU supervised the overall research process. MC-P, SB, RR and RU drafted the manuscript. All authors have critically reviewed and approved the manuscript.

  • Funding This research was funded through the Spanish Ministerio de Ciencia, Innovación y Universidades MICIU/AEI/ 10.13039/501100011033 and by ERDF/EU (PID2019-107188RB-C21 and PID2022-141461OB-I00), the Instituto de Salud Carlos III-CIBERER (ACCI19P2AC720-1), the AGAUR agency of the Catalan Government (2021SGR: 01093) and donations from Associació Síndrome Opitz C and Asociación Española del Síndrome Schaaf-Yang (AESYS). MC-P is supported by a Carmen de Torres fellowship from IRSJD and AP-P and EA-C are recipients of a FPU fellowship from Spanish Ministerio de Universidades.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.