Biallelic Cys141Tyr variant of SEL1L is associated with neurodevelopmental disorders, agammaglobulinemia, and premature death
Denisa Weis, … , Johannes A. Mayr, Ling Qi
Denisa Weis, … , Johannes A. Mayr, Ling Qi
Published November 9, 2023
Citation Information: J Clin Invest. 2024;134(2):e170882. https://doi.org/10.1172/JCI170882.
View: Text | PDF
Research Article Cell biology

Biallelic Cys141Tyr variant of SEL1L is associated with neurodevelopmental disorders, agammaglobulinemia, and premature death

Abstract

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.

Authors

Denisa Weis, Liangguang L. Lin, Huilun H. Wang, Zexin Jason Li, Katarina Kusikova, Peter Ciznar, Hermann M. Wolf, Alexander Leiss-Piller, Zhihong Wang, Xiaoqiong Wei, Serge Weis, Katarina Skalicka, Gabriela Hrckova, Lubos Danisovic, Andrea Soltysova, Tingxuan T. Yang, René Günther Feichtinger, Johannes A. Mayr, Ling Qi

×

Figure 4

SEL1LC141Y causes severe ERAD dysfunction, but not an overt UPR.

Options: View larger image (or click on image) Download as PowerPoint
SEL1LC141Y causes severe ERAD dysfunction, but not an overt UPR. (A and...
(A and B) Western blot analysis of SEL1L, HRD1, and endogenous ERAD substrates in various KI HEK293T cells expressing different variants, with quantitation shown (B) (n = 3–4 per group). (C) Western blot analysis of ER chaperones in WT and SEL1LC141Y patient fibroblasts with quantitation shown below (n = 4–6 per group). (D) Western blot analysis of IRE1α phosphorylation using Phos-tag gel in WT and SEL1LC141Y patient fibroblasts treated with and without 10 μM MG132 for 2 hours (n = 3 per group). Tg, thapsigargin, ER stress inducer. (E) Reverse transcription PCR (RT-PCR) of XBP1 splicing levels in WT and SEL1LC141Y patient fibroblasts treated with and without 10 μM MG132 for 2 hours. Two independent repeats. u, unsplicing; s, splicing. (F and G) Western blot analysis of PERK and eIF2α phosphorylation in WT and SEL1LC141Y patient fibroblasts treated with and without 10 μM MG132 for 2 hours, with quantitation shown (G) (n = 3 per group). p, phosphorylation. n, individual cell samples. Data are represented as means ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001, 2-tailed Student’s t test (B, CD147 protein level comparison between WT and P398L cells; C); 1-way ANOVA followed by Tukey’s post hoc test (B, comparison between WT and other variants; G).