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.
Denisa Weis  1  2 ,  Liangguang L Lin  3  4 ,  Huilun H Wang  3  4 ,  Zexin Jason Li  3  5 ,  Katarina Kusikova  6 ,  Peter Ciznar  2 ,  Hermann M Wolf  7  8 ,  Alexander Leiss-Piller  7 ,  Zhihong Wang  3  4 ,  Xiaoqiong Wei  3  4 ,  Serge Weis  9 ,  Katarina Skalicka  2 ,  Gabriela Hrckova  2 ,  Lubos Danisovic  10 ,  Andrea Soltysova  11  12 ,  Tingxuan T Yang  4 ,  René Günther Feichtinger  13 ,  Johannes A Mayr  13 ,  Ling Qi  3  4  5
Affiliations
  • 1. Department of Medical Genetics, Kepler University Hospital, School of Medicine, Johannes Kepler University, Linz, Austria.
  • 2. Department of Pediatrics, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia.
  • 3. Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, USA.
  • 4. Department of Molecular & Integrative Physiology and.
  • 5. Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, USA.
  • 6. Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia.
  • 7. Immunology Outpatient Clinic, Vienna, Austria.
  • 8. Sigmund Freud Private University-Medical School, Vienna, Austria.
  • 9. Division of Neuropathology, Neuromed Campus, Department of Pathology and Molecular Pathology, Kepler University Hospital, Johannes Kepler University, Linz, Austria.
  • 10. Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, and.
  • 11. Faculty of Natural Sciences, Department of Molecular Biology, Comenius University, Bratislava, Slovakia.
  • 12. Institute for Clinical and Translational Research, Biomedical Research Centre, Slovak Academy of Sciences, Bratislava, Slovakia.
  • 13. University Children's Hospital, Salzburger Landeskliniken Universitätsklinikum (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria.
PMID: 37943617 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.