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.

中文翻译：

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SEL1L-HRD1 ER 相关降解的亚形变体与神经发育障碍相关

最近使用细胞类型特异性敲除小鼠模型的研究提高了我们对 lin-12 样 HMG-CoA 还原酶降解 1 (SEL1L-HRD1) 内质网相关（ER 相关）降解 (ERAD) 抑制因子的病理生理学相关性的理解）；然而，它对人类的重要性仍不清楚，因为尚未发现任何疾病变异。在这里，我们报告了来自 3 个独立家庭的 6 名儿童的SEL1L和HRD1（或SYVN1 ）的 3 个双等位基因错义变异的鉴定，这些儿童表现出发育迟缓、智力障碍、小头畸形、面部畸形、肌张力减退和/或共济失调。这些SEL1L (p.Gly585Asp、p.Met528Arg) 和HRD1 (p.Pro398Leu) 变体在 ERAD 的不同步骤中表现出低效性和 ERAD 功能受损，包括底物募集 (SEL1L p.Gly585Asp)、SEL1L-HRD1 复合物形成 (SEL1L p.1)。 Met528Arg) 和 HRD1 活性 (HRD1 p.Pro398Leu)。我们的研究不仅提供了对 SEL1L-HRD1 ERAD 结构与功能关系的见解，而且还确立了 SEL1L-HRD1 ERAD 在人类中的重要性。