Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders
Huilun H. Wang, Liangguang L. Lin, Zexin J. Li, Xiaoqiong Wei, Omar Askander, Gerarda Cappuccio, Mais O. Hashem, Laurence Hubert, Arnold Munnich, Mashael Alqahtani, Qi Pang, Margit Burmeister, You Lu, Karine Poirier, Claude Besmond, Shengyi Sun, Nicola Brunetti-Pierri, Fowzan S. Alkuraya, Ling Qi
Huilun H. Wang, Liangguang L. Lin, Zexin J. Li, Xiaoqiong Wei, Omar Askander, Gerarda Cappuccio, Mais O. Hashem, Laurence Hubert, Arnold Munnich, Mashael Alqahtani, Qi Pang, Margit Burmeister, You Lu, Karine Poirier, Claude Besmond, Shengyi Sun, Nicola Brunetti-Pierri, Fowzan S. Alkuraya, Ling Qi
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Research Article Cell biology

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.

Authors

Huilun H. Wang, Liangguang L. Lin, Zexin J. Li, Xiaoqiong Wei, Omar Askander, Gerarda Cappuccio, Mais O. Hashem, Laurence Hubert, Arnold Munnich, Mashael Alqahtani, Qi Pang, Margit Burmeister, You Lu, Karine Poirier, Claude Besmond, Shengyi Sun, Nicola Brunetti-Pierri, Fowzan S. Alkuraya, Ling Qi

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Figure 4

Sequence and structural analyses of SEL1L and HRD1 variants.

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Sequence and structural analyses of SEL1L and HRD1 variants. (A–C) The a...
(A–C) The aa sequence alignment of SEL1L (A and B) and HRD1 (C) showing the conservation of residues across species. (D–F) PSSM scores for aa position in SEL1L (D and E) and HRD1 proteins (F), with WT in green and variants in red. (G–K) Schematic diagrams of human SEL1L (G) and HRD1 (K) with the location of the variants indicated. SP, signal peptide; FNII, fibronectin type II domain; SLR-N/M/C, Sel1-like repeats at N-terminal, middle-, and C-terminal; TM, transmembrane; CYTO, cytosol; RING, RING domain; Pro-rich, Proline-rich domain. (H–J) Structural prediction of human SEL1L/OS9/HRD1/DERLIN ERAD complex using AlphaFold2 with close-up views of SEL1L-M528 (blue) and G585 (green) areas shown in I and J. Red (dotted) line marks the putative substrate binding groove. (L) Comparison of disordered region of HRD1 across species, highlighting the disordered nature of the proline-rich domain.