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 1

Identification of SEL1LC141Y variant in humans using whole-exome sequencing.

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Identification of SEL1LC141Y variant in humans using whole-exome sequenc...
(A) Family pedigrees for the kindreds from Slovakia (2 consanguineous pairs) for SEL1L p.C141Y, showing autosomal recessive inheritance. Arrows point to probands. Black shapes indicate affected patients and gray shapes show a newborn died from holoprosencephaly. The age indicated is as of 2022 or at time of death (cross). Photos of the patients are shown below. Photo of patient 1 was published in the book Pediatrics (51) to show marasmus and is republished here with permission. (B) Genetic analysis pipeline of whole-exome sequencing (WES) data for patients 3 and 5 (IV-3/6) and their parents, III-3/4. (C and D) Exonic and chromosomal locations of SEL1L variant (C), with Sanger sequencing in patients and other family members (D). R, heterozygosity; C, cysteine; Y, tyrosine.