[HTML][HTML] Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders
The Journal of Clinical Investigation, 2024•Am Soc Clin Investig
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 …
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 …
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.
The Journal of Clinical Investigation