内质网相关蛋白降解
生物
内质网
遗传学
未折叠蛋白反应
作者
Huilun Wang,Liangguang Leo Lin,Zexin Jason Li,Xiaoqiong Wei,Omar Askander,Gerarda Cappuccio,Mais Hashem,Laurence Hubert,Arnold Münnich,Mashael Alqahtani,Qi Pang,Margit Burmeister,You Lu,Karine Poirier,Claude Besmond,Shengyi Sun,Nicola Brunetti‐Pierri,Fowzan S. Alkuraya,Ling Qi
摘要
Recent studies using cell type-specific knockout mouse models have improved our understanding of the pathophysiological relevance of SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD); however, its importance in humans remains unclear as no disease variant has been identified. Here we report the identification of three bi-allelic missense variants of SEL1L and HRD1 (or SYVN1) in six children from three independent families presenting with developmental delay, intellectual disability, microcephaly, facial dysmorphisms, hypotonia and/or ataxia. These SEL1L (p.Gly585Asp, p.Met528Arg) and HRD1 (p.Pro398Leu) variants were hypomorphic and impaired ERAD function at distinct steps of ERAD including substrate recruitment (SEL1L p.Gly585Asp), SEL1L-HRD1 complex formation (SEL1L p.Met528Arg), and HRD1 activity (HRD1 p.Pro398Leu). Our study not only provide new insights into the structure-function relationship of SEL1L-HRD1 ERAD, but also establish the importance of SEL1L-HRD1 ERAD in humans.
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