%0 Journal Article
%T Subcellular localisation of truncated MAGEL2 proteins: insight into the molecular pathology of Schaaf-Yang syndrome.
%A Centeno-Pla M
%A Alcaide-Consuegra E
%A Gibson S
%A Prat-Planas A
%A Gutiérrez-Ávila JD
%A Grinberg D
%A Urreizti R
%A Rabionet R
%A Balcells S
%J J Med Genet
%V 61
%N 8
%D 2024 Jul 19
%M 38548315
%F 5.941
%R 10.1136/jmg-2024-109898
%X 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.