학술논문
Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders.
Document Type
Article
Author
Wang, Huilun H.; Lin, Liangguang L.; J. Li, Zexin; Xiaoqiong Wei; Askander, Omar; Cappuccio, Gerarda; Hashem, Mais O.; Hubert, Laurence; Munnich, Arnold; Alqahtani, Mashael; Qi Pang; Burmeister, Margit; You Lu; Poirier, Karine; Besmond, Claude; Shengyi Sun; Brunetti-Pierri, Nicola; Alkuraya, Fowzan S.; Ling Qi
Source
Subject
*CHILDREN with developmental disabilities
*MISSENSE mutation
*NEURAL development
*ENDOPLASMIC reticulum
*DEVELOPMENTAL delay
*INTELLECTUAL disabilities
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Language
ISSN
0021-9738
Abstract
Recent studies using cell type--specific knockout mouse models have improved our understanding of the pathophysiological relevance of suppressor of lin-12-like--HMG-CoA reductase degradation 1 (SEL1L-HRD1) endoplasmic reticulum--associated (ER-associated) degradation (ERAD); however, its importance in humans remains unclear, as no disease variant has been identified. Here, we report the identification of 3 biallelic missense variants of SEL1L and HRD1 (or SYVN1) in 6 children from 3 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 provides insights into the structure-function relationship of SEL1L-HRD1 ERAD, but also establishes the importance of SEL1L-HRD1 ERAD in humans. [ABSTRACT FROM AUTHOR]