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.
摘要：
Schaaf-Yang综合征（SYS）是一种超罕见的神经发育障碍，由野生型（WT）或截短的MAGEL2异源表达中的截断突变引起（p。Gln638*）C端HA标记的MAGEL2揭示了截短的蛋白质变体从主要细胞质向更细胞核定位的转变。现在，我们将此分析扩展到N端FLAG标记的MAGEL2上的六个其他SYS突变。我们的结果复制并扩展了我们以前的发现，显示所有截短的MAGEL2蛋白始终显示出主要的核定位，不考虑C-末端或N-末端位置和标签的化学性质。与多重先天性关节炎相关的变体显示出更明显的核保留表型，提示临床严重程度与核错位程度之间存在相关性。这些结果表明截短的MAGEL2的新形态效应，这可能有助于SYS的发病机理。
