截短的 MAGEL2 蛋白的亚细胞定位:洞察沙夫-杨综合征的分子病理学。

IF 3.5 2区 医学 Q2 GENETICS & HEREDITY Journal of Medical Genetics Pub Date : 2024-07-19 DOI:10.1136/jmg-2024-109898
Mónica Centeno-Pla, Estefanía Alcaide-Consuegra, Sophie Gibson, Aina Prat-Planas, Juan Diego Gutiérrez-Ávila, Daniel Grinberg, Roser Urreizti, Raquel Rabionet, Susanna Balcells
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引用次数: 0

摘要

野生型(WT)或截短的(p.Gln638*)C-端 HA 标记 MAGEL2 的异源表达显示,截短蛋白变体从主要的细胞质定位转变为更多的核定位。现在,我们将这一分析扩展到 N 端 FLAG 标记的 MAGEL2 上的另外六个 SYS 突变。我们的结果重复并扩展了之前的发现,表明所有截短的 MAGEL2 蛋白都始终显示出主要的核定位,而与 C 端或 N 端位置以及标签的化学性质无关。与先天性多关节发育不良相关的变体显示出更明显的核滞留表型,表明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具有新形效应,可能有助于SYS的发病。
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Subcellular localisation of truncated MAGEL2 proteins: insight into the molecular pathology of Schaaf-Yang syndrome.

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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来源期刊
Journal of Medical Genetics
Journal of Medical Genetics 医学-遗传学
CiteScore
7.60
自引率
2.50%
发文量
92
审稿时长
4-8 weeks
期刊介绍: Journal of Medical Genetics is a leading international peer-reviewed journal covering original research in human genetics, including reviews of and opinion on the latest developments. Articles cover the molecular basis of human disease including germline cancer genetics, clinical manifestations of genetic disorders, applications of molecular genetics to medical practice and the systematic evaluation of such applications worldwide.
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