: Recent studies using cell type-specific knockout mouse models have improved our understanding of the pathophysiological relevance of SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD); however, its importance in humans remains unclear as no disease variant has been identified. Here we report the identification of three bi-allelic missense variants of SEL1L and HRD1 (or SYVN1) in six children from three 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 provide new insights into the structure-function relationship of SEL1L-HRD1 ERAD, but also establish the importance of SEL1L-HRD1 ERAD in humans.
Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders / Wang, H.H., Lin, L.L., Li, Z.J., Wei, X., Askander, O., Cappuccio, G., Hashem, M.O., Hubert, L., Munnich, A., Alqahtani, M., Pang, Q.i., Burmeister, M., Lu, Y., Poirier, K., Besmond, C., Sun, S., Brunetti-Pierri, N., Alkuraya, F.S., Qi, L.. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 1558-8238. - 134:2(2024). [10.1172/JCI170054]
Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders
Cappuccio, Gerarda;Brunetti-Pierri, Nicola;
2024
Abstract
: Recent studies using cell type-specific knockout mouse models have improved our understanding of the pathophysiological relevance of SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD); however, its importance in humans remains unclear as no disease variant has been identified. Here we report the identification of three bi-allelic missense variants of SEL1L and HRD1 (or SYVN1) in six children from three 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 provide new insights into the structure-function relationship of SEL1L-HRD1 ERAD, but also establish the importance of SEL1L-HRD1 ERAD in humans.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
