{"doi":"10.1172/jci170054","title":"Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders","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.","journal":"Journal of Clinical Investigation","year":2023,"id":324847,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":33,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9623,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":655124,"name":"Liangguang Leo Lin","orcid":"0000-0003-1414-610X","position":1,"is_corresponding":false},{"id":1042327,"name":"Zexin Jason Li","orcid":null,"position":2,"is_corresponding":false},{"id":409331,"name":"Xiaoqiong Wei","orcid":"0000-0001-7576-4820","position":3,"is_corresponding":false},{"id":1042328,"name":"Omar Askander","orcid":null,"position":4,"is_corresponding":false},{"id":243311,"name":"Gerarda Cappuccio","orcid":"0000-0003-3934-2342","position":5,"is_corresponding":false},{"id":354569,"name":"Mais O. Hashem","orcid":null,"position":6,"is_corresponding":false},{"id":779563,"name":"Laurence Hubert","orcid":"0000-0003-2598-159X","position":7,"is_corresponding":false},{"id":779564,"name":"Arnold Münnich","orcid":"0000-0001-6117-7588","position":8,"is_corresponding":false},{"id":509557,"name":"Mashael Alqahtani","orcid":"0000-0003-1582-2878","position":9,"is_corresponding":false},{"id":1041681,"name":"Qi Pang","orcid":"0000-0001-8333-5647","position":10,"is_corresponding":false},{"id":244502,"name":"Margit Burmeister","orcid":"0000-0002-1914-2434","position":11,"is_corresponding":false},{"id":865749,"name":"You Lu","orcid":"0000-0002-0075-8167","position":12,"is_corresponding":false},{"id":540911,"name":"Karine Poirier","orcid":"0000-0002-7928-2906","position":13,"is_corresponding":false},{"id":779571,"name":"Claude Besmond","orcid":"0000-0001-9073-8225","position":14,"is_corresponding":false},{"id":345637,"name":"Shengyi Sun","orcid":"0000-0002-1734-3902","position":15,"is_corresponding":false},{"id":243314,"name":"Nicola Brunetti‐Pierri","orcid":"0000-0002-6895-8819","position":16,"is_corresponding":false},{"id":291081,"name":"Fowzan S. Alkuraya","orcid":"0000-0003-4158-341X","position":17,"is_corresponding":false},{"id":244412,"name":"Ling Qi","orcid":"0000-0001-8229-0184","position":18,"is_corresponding":false},{"id":357093,"name":"Huilun Wang","orcid":"0000-0002-0583-1386","position":0,"is_corresponding":true}],"reference_count":87,"raw_metadata":null,"created_at":"2026-07-19T01:08:16.809511Z","pmid":"37943610","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}