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

J Clin Invest. 2024 Jan 16;134(2):e170882. doi: 10.1172/JCI170882.

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: Adaptive immunity; Cell Biology; Genetic diseases; Protein misfolding.

MeSH terms

  • Agammaglobulinemia* / genetics
  • Animals
  • Endoplasmic Reticulum-Associated Degradation
  • Humans
  • Mice
  • Mortality, Premature
  • Proteins* / metabolism
  • Ubiquitin-Protein Ligases / genetics

Substances

  • Proteins
  • Ubiquitin-Protein Ligases
  • SEL1L protein, human