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

Autor: Wang HH; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, University of Virginia, Charlottesville, Virginia, USA.; Department of Molecular & Integrative Physiology and., Lin LL; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, University of Virginia, Charlottesville, Virginia, USA.; Department of Molecular & Integrative Physiology and., Li ZJ; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, University of Virginia, Charlottesville, Virginia, USA.; Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, USA., Wei X; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, University of Virginia, Charlottesville, Virginia, USA.; Department of Molecular & Integrative Physiology and., Askander O; Hopital Cheik Zaïd, Hopital Universitaire International RABAT, Morocco., Cappuccio G; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.; Department of Translational Medicine, University of Naples Federico II, Naples, Italy., Hashem MO; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Hubert L; Imagine Institute, INSERM UMR1163, Paris, France.; Université Paris Cité, Paris, France., Munnich A; Imagine Institute, INSERM UMR1163, Paris, France., Alqahtani M; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia., Pang Q; Department of Neurosurgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China., Burmeister M; Michigan Neuroscience Institute and Departments of Computational Medicine & Bioinformatics, Psychiatry, and Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA., Lu Y; Department of Molecular & Integrative Physiology and., Poirier K; Imagine Institute, INSERM UMR1163, Paris, France., Besmond C; Imagine Institute, INSERM UMR1163, Paris, France., Sun S; Department of Pharmacology, University of Virginia, Charlottesville, Virginia, USA., Brunetti-Pierri N; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.; Department of Translational Medicine, University of Naples Federico II, Naples, Italy.; Scuola Superiore Meridionale (SSM, School of Advanced Studies), Genomics and Experimental Medicine Program, University of Naples Federico II, Naples, Italy., Alkuraya FS; Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.; Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia., Qi L; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, University of Virginia, Charlottesville, Virginia, USA.; Department of Molecular & Integrative Physiology and.; Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, USA.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2024 Jan 16; Vol. 134 (2). Date of Electronic Publication: 2024 Jan 16.
DOI: 10.1172/JCI170054
Abstrakt: 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.
Databáze: MEDLINE