{Reference Type}: Journal Article
{Title}: Subcellular localisation of truncated MAGEL2 proteins: insight into the molecular pathology of Schaaf-Yang syndrome.
{Author}: Centeno-Pla M;Alcaide-Consuegra E;Gibson S;Prat-Planas A;Gutiérrez-Ávila JD;Grinberg D;Urreizti R;Rabionet R;Balcells S;
{Journal}: J Med Genet
{Volume}: 61
{Issue}: 8
{Year}: 2024 Jul 19
{Factor}: 5.941
{DOI}: 10.1136/jmg-2024-109898
{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.