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.
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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 6

SEL1L FNII domain itself is dispensable for ERAD function.

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SEL1L FNII domain itself is dispensable for ERAD function. (A) Schematic...
(A) Schematic diagrams of human full-length and FNII truncated (ΔFNII, 115–170 aa) SEL1L and its homolog Hrd3 in drosophila and yeast with the epitopes recognized by either homemade or Abcam (ab78298) SEL1L antibodies indicated. SP, signal peptide; SLR-N/M/C, Sel1-like repeats at N-, middle-, and C-terminal; TM, transmembrane; Orange lines indicate 2 disulfide bonds. (B–D) Western blot analysis of ERAD proteins and endogenous ERAD substrates in WT, SEL1L variants KI, ΔFNII, SEL1L–/–, and SEL1LWT/ΔFNII (ΔFNII HET) HEK293T cells, with quantitation shown (D). n = 5–11 (WT); n = 3–9 (SEL1LC141Y); n = 3–8 (SEL1LC127Y); n = 4–10 (ΔFNII); n = 3–6 (SEL1L–/–) independent samples. OS9 1 indicates isoform OS-9.1; OS9 2 indicates isoform OS-9.2. Both bands were quantitated together. (E and F) Cycloheximide chase analysis of ERAD proteins and endogenous ERAD substrates in various KI HEK293T cells, with quantitation shown (F). n = 4–9 (WT); n = 3–5 (ΔFNII); n = 3–5 (SEL1LC141Y). Data are represented as means ± SEM. *P < 0.05; **P < 0.01; ****P < 0.0001, 1-way ANOVA followed by Tukey’s post hoc test (D); 2-way ANOVA followed by Tukey’s multiple-comparisons test (F).