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 2

Clinical features of patients carrying SEL1L and HRD1 variants.

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Clinical features of patients carrying SEL1L and HRD1 variants. (A, C, E...
(A, C, E) Photos of patient 1 (A), patient 2 (C), and patient 6 (E) showing clumsy and wide gait, with need of external supports in C and E. (B, D, and F) Photos of the patients showing dysmorphisms (red arrows). (B) Patient 1 at 13 years (left, middle) and 11 years (right) of age, showing overbite (left, middle), downslanting palpebral fissures, and pectus excavatum (right). (D) Patients 2–5 at ages of 17 (patient 2), 15 (patient 3), 11 (patient 4), and 5 years (patient 5), showing overbite (patients 2 and 3) and downslanting palpebral fissures (patient 2–5). (F) Patient 6 at 16 years old, showing hypertelorism and flat nasal bridge (right).