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

  • J Clin Invest. 2024 Jan 16;134(2):e170054. doi: 10.1172/JCI170054.
Huilun H Wang  1  2 ,  Liangguang L Lin  1  2 ,  Zexin J Li  1  3 ,  Xiaoqiong Wei  1  2 ,  Omar Askander  4 ,  Gerarda Cappuccio  5  6 ,  Mais O Hashem  7 ,  Laurence Hubert  8  9 ,  Arnold Munnich  8 ,  Mashael Alqahtani  7 ,  Qi Pang  10 ,  Margit Burmeister  11 ,  You Lu  2 ,  Karine Poirier  8 ,  Claude Besmond  8 ,  Shengyi Sun  12 ,  Nicola Brunetti-Pierri  5  6  13 ,  Fowzan S Alkuraya  7  14 ,  Ling Qi  1  2  3
Affiliations
  • 1. Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, University of Virginia, Charlottesville, Virginia, USA.
  • 2. Department of Molecular & Integrative Physiology and.
  • 3. Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, USA.
  • 4. Hopital Cheik Zaïd, Hopital Universitaire International RABAT, Morocco.
  • 5. Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
  • 6. Department of Translational Medicine, University of Naples Federico II, Naples, Italy.
  • 7. Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • 8. Imagine Institute, INSERM UMR1163, Paris, France.
  • 9. Université Paris Cité, Paris, France.
  • 10. Department of Neurosurgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
  • 11. Michigan Neuroscience Institute and Departments of Computational Medicine & Bioinformatics, Psychiatry, and Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, USA.
  • 12. Department of Pharmacology, University of Virginia, Charlottesville, Virginia, USA.
  • 13. Scuola Superiore Meridionale (SSM, School of Advanced Studies), Genomics and Experimental Medicine Program, University of Naples Federico II, Naples, Italy.
  • 14. Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
PMID: 37943610 DOI: 10.1172/JCI170054
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.

Keywords
Cell Biology; Genetic variation; Neurological disorders; Protein misfolding.