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

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Figure 7

SEL1LC141Y variant causes proteasome-mediated self-destruction of SEL1L-HRD1 ERAD complex.

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SEL1LC141Y variant causes proteasome-mediated self-destruction of SEL1L...
(A) Western blot analysis of SEL1L and HRD1 in WT and SEL1LC141Y patient fibroblasts treated with and without 10 μM MG132 for 2 hours, with quantitation shown in Supplemental Figure 9A. n = 6–8 (WT); n = 3–4 (C141Y). (B and C) Western blot analysis of ERAD proteins and endogenous ERAD substrates in WT or KI HEK293T cells with and without HRD1–/– or RNF5–/–, with quantitation shown in C and Supplemental Figure 9, C and E (n = 3–9 per group). (D) Western blot analysis of HRD1 in WT or KI HEK293T cells with and without HRD1–/– using 2 different SEL1L antibodies, with quantitation shown in Supplemental Figure 9B (n = 3–6 per group). (E and F) Cycloheximide chase analysis of ERAD proteins in WT and KI HEK293T cells with and without HRD1–/–, with quantitation shown (F) (n = 3–6 per group). OS9 1 indicates isoform OS-9.1; OS9 2 indicates isoform OS-9.2. Both bands were quantitated together. (G) Reducing and nonreducing SDS-PAGE and Western blot analysis of HMW aggregates of SEL1L in KI HEK293T cells with and without HRD1–/– (representative of 2 repeats). Data are represented as means ± SEM. **P < 0.01; ***P < 0.001; ****P < 0.0001, 1-way ANOVA followed by Tukey’s post hoc test (C); 2-way ANOVA followed by Tukey’s multiple-comparisons test (F).