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.
Journal article
2024-07-19T00:00:00+00:00
61
780 - 782
2
Clinical genetics, Gain of Function Mutation, Mutation, Nervous System Diseases, Humans, Cell Nucleus, Neoplasm Proteins, Mutation, Phenotype, Arthrogryposis, Cytoplasm, Neurodevelopmental Disorders, Protein Transport, HEK293 Cells, Hypopituitarism, Facies, Intracellular Signaling Peptides and Proteins, Intrinsically Disordered Proteins, Imprinting Disorders, Developmental Disabilities, Chromosome Disorders