Journal Article

Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders

Hubert, Laurence, Lin, Liangguang L., Burmeister, Margit, Wang, Huilun H., Hashem, Mais O., Alkuraya, Fowzan S., Brunetti-Pierri, Nicola, Qi, Ling, Alqahtani, Mashael, Sun, Shengyi, Besmond, Claude, Li, Zexin J., Askander, Omar, Pang, Qi, Munnich, Arnold, Cappuccio, Gerarda, Wei, Xiaoqiong, Lu, You, Poirier, Karine

2024

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Age / Animal models / Animals / Ataxia / B cells / Causes of / Cell biology / Cell culture / Child / Child development / Child development deviations / Degradation / Development and progression / Developmental disabilities / Endoplasmic reticulum / Endoplasmic Reticulum-Associated Degradation - genetics / Family / Gait / Genetic aspects / Genetic variation / Health aspects / Homeostasis / Humans / Intellectual disabilities / LIN-12 protein / Mice / Mice, Knockout / Microcephaly / Microencephaly / Nervous system diseases / Neurodevelopmental disorders / Neurodevelopmental Disorders - genetics / Neurological research / Neurophysiology / Parents & parenting / Patients / Physiology / Proteins / Proteins - metabolism / Siblings / Structure-function relationships / Ubiquitin-Protein Ligases - genetics