Subcellular localisation of truncated MAGEL2 proteins: insight into the molecular pathology of Schaaf-Yang syndrome

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Abstract

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.

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Centeno-Pla, M., Alcaide-Consuegra, E., Gibson, S., Prat-Planas, A., Gutiérrez-Ávila, J. D., Grinberg, D., … Balcells, S. (2024). Subcellular localisation of truncated MAGEL2 proteins: insight into the molecular pathology of Schaaf-Yang syndrome. Journal of Medical Genetics. https://doi.org/10.1136/jmg-2024-109898

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