Suppressor of lin-12-like–HMG-CoA reductase degradation 1 (SEL1L-HRD1) ER-associated degradation (ERAD) plays a critical role in many physiological processes in mice, including immunity, water homeostasis, and energy metabolism; however, its relevance and importance in humans remain unclear, as no disease variant has been identified. Here, we report a biallelic SEL1L variant (p. Cys141Tyr) in 5 patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. This variant disrupted the formation of a disulfide bond in the luminal fibronectin II domain of SEL1L, largely abolishing the function of the SEL1L-HRD1 ERAD complex in part via proteasomal-mediated self destruction by HRD1. This study reports a disease entity termed ENDI-agammaglobulinemia (ENDI-A) syndrome and establishes an inverse correlation between SEL1L-HRD1 ERAD functionality and disease severity in humans.

中文翻译：

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SEL1L 的双等位基因 Cys141Tyr 变体与神经发育障碍、丙种球蛋白血症和过早死亡相关

lin-12-like-HMG-CoA 还原酶降解抑制剂 1 (SEL1L-HRD1) ER 相关降解 (ERAD) 在小鼠的许多生理过程中发挥着关键作用，包括免疫、水稳态和能量代谢；然而，它对人类的相关性和重要性仍不清楚，因为尚未发现任何疾病变异。在这里，我们报告了来自斯洛伐克近亲家庭的 5 名患者的双等位基因SEL1L变异（p. Cys141Tyr）。这些患者不仅出现婴儿期发病 (ENDI) 综合征的 ERAD 相关神经发育障碍，还出现婴儿期发病的无丙种球蛋白血症，且没有成熟 B 细胞，导致频繁感染和早期死亡。该变体破坏了 SEL1L 管腔纤连蛋白 II 结构域中二硫键的形成，部分通过 HRD1 蛋白酶体介导的自我破坏，很大程度上废除了 SEL1L-HRD1 ERAD 复合物的功能。这项研究报告了一种称为 ENDI-无丙种球蛋白血症 (ENDI-A) 综合征的疾病实体，并建立了 SEL1L-HRD1 ERAD 功能与人类疾病严重程度之间的负相关性。