Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:134 |
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| Enthalten in: |
The Journal of clinical investigation - 134(2024), 2 vom: 16. Jan. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wang, Huilun H [VerfasserIn] |
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| Links: |
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| Themen: |
Cell Biology |
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| Anmerkungen: |
Date Completed 26.01.2024 Date Revised 10.02.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1172/JCI170054 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM364353317 |
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| 100 | 1 | |a Wang, Huilun H |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders |
| 264 | 1 | |c 2024 | |
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| 500 | |a Date Completed 26.01.2024 | ||
| 500 | |a Date Revised 10.02.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Cell Biology | |
| 650 | 4 | |a Genetic variation | |
| 650 | 4 | |a Neurological disorders | |
| 650 | 4 | |a Protein misfolding | |
| 650 | 7 | |a Proteins |2 NLM | |
| 650 | 7 | |a SEL1L protein, human |2 NLM | |
| 650 | 7 | |a Ubiquitin-Protein Ligases |2 NLM | |
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| 650 | 7 | |a SYVN1 protein, human |2 NLM | |
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| 700 | 1 | |a Lin, Liangguang L |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Zexin J |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Xiaoqiong |e verfasserin |4 aut | |
| 700 | 1 | |a Askander, Omar |e verfasserin |4 aut | |
| 700 | 1 | |a Cappuccio, Gerarda |e verfasserin |4 aut | |
| 700 | 1 | |a Hashem, Mais O |e verfasserin |4 aut | |
| 700 | 1 | |a Hubert, Laurence |e verfasserin |4 aut | |
| 700 | 1 | |a Munnich, Arnold |e verfasserin |4 aut | |
| 700 | 1 | |a Alqahtani, Mashael |e verfasserin |4 aut | |
| 700 | 1 | |a Pang, Qi |e verfasserin |4 aut | |
| 700 | 1 | |a Burmeister, Margit |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, You |e verfasserin |4 aut | |
| 700 | 1 | |a Poirier, Karine |e verfasserin |4 aut | |
| 700 | 1 | |a Besmond, Claude |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Shengyi |e verfasserin |4 aut | |
| 700 | 1 | |a Brunetti-Pierri, Nicola |e verfasserin |4 aut | |
| 700 | 1 | |a Alkuraya, Fowzan S |e verfasserin |4 aut | |
| 700 | 1 | |a Qi, Ling |e verfasserin |4 aut | |
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