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

• Published in: The Journal of clinical investigation Vol. 134; no. 2; pp. 1 - 15
• Main Authors: Wang, Huilun H, Lin, Liangguang L, Li, Zexin J, Wei, Xiaoqiong, Askander, Omar, Cappuccio, Gerarda, Hashem, Mais O, Hubert, Laurence, Munnich, Arnold, Alqahtani, Mashael, Pang, Qi, Burmeister, Margit, Lu, You, Poirier, Karine, Besmond, Claude, Sun, Shengyi, Brunetti-Pierri, Nicola, Alkuraya, Fowzan S, Qi, Ling
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 16.01.2024
• Subjects: Age; Animal models; Animals; Ataxia; B cells; Causes of; 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; Saudi Arabia; Morocco; France; Virginia; United States; Protein misfolding; Genetic variation; Neurological disorders; Cell Biology
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI170054

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.