Hypomorphic Variants of SEL1L-HRD1 ER-associated Degradation Are Associated with Neurodevelopmental Disorders

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2023 Nov 9

PMID 37943610

Authors

Huilun H Wang

Liangguang L Lin

Zexin J Li

Xiaoqiong Wei

Omar Askander

Gerarda Cappuccio

Mais O Hashem

Laurence Hubert

Arnold Munnich

Mashael Alqahtani

Qi Pang

Margit Burmeister

You Lu

Karine Poirier

Claude Besmond

Shengyi Sun

Nicola Brunetti-Pierri

Fowzan S Alkuraya

Ling Qi

Affiliations

Soon will be listed here.

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.

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