Research & Innovation
Publications
Biallelic Cys141Tyr variant of SEL1L is associated with neurodevelopmental disorders, agammaglobulinemia, and premature death
PMU Authors
René Günther Feichtinger, Johannes A Mayr
All 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
Journal association
JOURNAL OF CLINICAL INVESTIGATION
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.
Keywords
Humans, Animals, MICE, PROTEINS, ENDOPLASMIC-RETICULUM, Proteins/metabolism, Ubiquitin-Protein Ligases/genetics, Endoplasmic Reticulum-Associated Degradation, Agammaglobulinemia/genetics, Mortality, Premature, Synoviolin, Reticulum-associated degradation, Sel1l, Er-associated degradation