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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 Article has an altmetric score of 6

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

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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 2

Sequence and structural analyses of SEL1LC141Y variant.

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Sequence and structural analyses of SEL1LC141Y variant.
(A) Schematic di...
(A) Schematic diagram of human SEL1L. SP, signal peptide; SLR-N/M/C, Sel1-like repeats at N-, middle-, and C-terminal; TM, transmembrane; CYTO, cytosol. Orange lines, 2 disulfide bonds (Cys127-Cys153, Cys141-Cys168). (B) The aa sequence alignment of SEL1L showing the conservation of SEL1L C141 residue (highlighted in orange) and neighboring cysteine residues (highlighted in gray) across species. (C) PSSM scores for position 141, with WT in green and variant in red. (D and E) Structural prediction of human SEL1L/OS9/HRD1/DERLIN ERAD complex using AlphaFold2 with close-up view of C141 residue and disulfide bonds (black arrows) (E).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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