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ResearchIn-Press PreviewCell biology Open Access | 10.1172/JCI170882

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

Denisa Weis,1 Liangguang Leo Lin,2 Huilun Helen Wang,2 Zexin Jason Li,2 Katarína Kušíková,3 Peter Ciznar,4 Hermann Maximillian Wolf,5 Alexander Leiss-Piller,5 Zhihong Wang,2 Xiaoqiong Wei,2 Serge Weis,6 Katarina Skalicka,4 Gabriela Hrckova,4 Lubos Danisovic,7 Andrea Soltysova,8 Tingxuan Tina Yang,9 René Günther Feichtinger,10 Johannes Adalbert Mayr,10 and Ling Qi2

1Department of Medical Genetics, Kepler University Hospital, Johannes kepler University, Linz, Austria

2Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

3Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

4Department of Pediatrics, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

5Immunology Outpatient Clinic, Immunology Outpatient Clinic, Vienna, Austria

6Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University, Linz, Austria

7Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Me, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

8Faculty of Natural Sciences, Department of Molecular Biology, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

9Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

10Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria

Find articles by Weis, D. in: JCI | PubMed | Google Scholar |

1Department of Medical Genetics, Kepler University Hospital, Johannes kepler University, Linz, Austria

2Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

3Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

4Department of Pediatrics, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

5Immunology Outpatient Clinic, Immunology Outpatient Clinic, Vienna, Austria

6Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University, Linz, Austria

7Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Me, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

8Faculty of Natural Sciences, Department of Molecular Biology, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

9Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

10Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria

Find articles by Lin, L. in: JCI | PubMed | Google Scholar |

1Department of Medical Genetics, Kepler University Hospital, Johannes kepler University, Linz, Austria

2Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

3Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

4Department of Pediatrics, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

5Immunology Outpatient Clinic, Immunology Outpatient Clinic, Vienna, Austria

6Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University, Linz, Austria

7Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Me, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

8Faculty of Natural Sciences, Department of Molecular Biology, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

9Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

10Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria

Find articles by Wang, H. in: JCI | PubMed | Google Scholar |

1Department of Medical Genetics, Kepler University Hospital, Johannes kepler University, Linz, Austria

2Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

3Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

4Department of Pediatrics, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

5Immunology Outpatient Clinic, Immunology Outpatient Clinic, Vienna, Austria

6Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University, Linz, Austria

7Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Me, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

8Faculty of Natural Sciences, Department of Molecular Biology, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

9Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

10Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria

Find articles by Li, Z. in: JCI | PubMed | Google Scholar

1Department of Medical Genetics, Kepler University Hospital, Johannes kepler University, Linz, Austria

2Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

3Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

4Department of Pediatrics, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

5Immunology Outpatient Clinic, Immunology Outpatient Clinic, Vienna, Austria

6Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University, Linz, Austria

7Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Me, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

8Faculty of Natural Sciences, Department of Molecular Biology, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

9Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

10Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria

Find articles by Kušíková, K. in: JCI | PubMed | Google Scholar

1Department of Medical Genetics, Kepler University Hospital, Johannes kepler University, Linz, Austria

2Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

3Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

4Department of Pediatrics, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

5Immunology Outpatient Clinic, Immunology Outpatient Clinic, Vienna, Austria

6Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University, Linz, Austria

7Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Me, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

8Faculty of Natural Sciences, Department of Molecular Biology, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

9Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

10Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria

Find articles by Ciznar, P. in: JCI | PubMed | Google Scholar |

1Department of Medical Genetics, Kepler University Hospital, Johannes kepler University, Linz, Austria

2Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

3Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

4Department of Pediatrics, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

5Immunology Outpatient Clinic, Immunology Outpatient Clinic, Vienna, Austria

6Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University, Linz, Austria

7Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Me, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

8Faculty of Natural Sciences, Department of Molecular Biology, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

9Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

10Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria

Find articles by Wolf, H. in: JCI | PubMed | Google Scholar |

1Department of Medical Genetics, Kepler University Hospital, Johannes kepler University, Linz, Austria

2Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

3Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

4Department of Pediatrics, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

5Immunology Outpatient Clinic, Immunology Outpatient Clinic, Vienna, Austria

6Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University, Linz, Austria

7Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Me, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

8Faculty of Natural Sciences, Department of Molecular Biology, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

9Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

10Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria

Find articles by Leiss-Piller, A. in: JCI | PubMed | Google Scholar

1Department of Medical Genetics, Kepler University Hospital, Johannes kepler University, Linz, Austria

2Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

3Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

4Department of Pediatrics, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

5Immunology Outpatient Clinic, Immunology Outpatient Clinic, Vienna, Austria

6Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University, Linz, Austria

7Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Me, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

8Faculty of Natural Sciences, Department of Molecular Biology, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

9Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

10Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria

Find articles by Wang, Z. in: JCI | PubMed | Google Scholar |

1Department of Medical Genetics, Kepler University Hospital, Johannes kepler University, Linz, Austria

2Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

3Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

4Department of Pediatrics, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

5Immunology Outpatient Clinic, Immunology Outpatient Clinic, Vienna, Austria

6Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University, Linz, Austria

7Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Me, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

8Faculty of Natural Sciences, Department of Molecular Biology, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

9Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

10Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria

Find articles by Wei, X. in: JCI | PubMed | Google Scholar |

1Department of Medical Genetics, Kepler University Hospital, Johannes kepler University, Linz, Austria

2Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

3Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

4Department of Pediatrics, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

5Immunology Outpatient Clinic, Immunology Outpatient Clinic, Vienna, Austria

6Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University, Linz, Austria

7Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Me, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

8Faculty of Natural Sciences, Department of Molecular Biology, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

9Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

10Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria

Find articles by Weis, S. in: JCI | PubMed | Google Scholar |

1Department of Medical Genetics, Kepler University Hospital, Johannes kepler University, Linz, Austria

2Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

3Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

4Department of Pediatrics, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

5Immunology Outpatient Clinic, Immunology Outpatient Clinic, Vienna, Austria

6Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University, Linz, Austria

7Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Me, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

8Faculty of Natural Sciences, Department of Molecular Biology, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

9Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

10Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria

Find articles by Skalicka, K. in: JCI | PubMed | Google Scholar

1Department of Medical Genetics, Kepler University Hospital, Johannes kepler University, Linz, Austria

2Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

3Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

4Department of Pediatrics, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

5Immunology Outpatient Clinic, Immunology Outpatient Clinic, Vienna, Austria

6Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University, Linz, Austria

7Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Me, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

8Faculty of Natural Sciences, Department of Molecular Biology, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

9Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

10Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria

Find articles by Hrckova, G. in: JCI | PubMed | Google Scholar

1Department of Medical Genetics, Kepler University Hospital, Johannes kepler University, Linz, Austria

2Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

3Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

4Department of Pediatrics, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

5Immunology Outpatient Clinic, Immunology Outpatient Clinic, Vienna, Austria

6Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University, Linz, Austria

7Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Me, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

8Faculty of Natural Sciences, Department of Molecular Biology, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

9Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

10Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria

Find articles by Danisovic, L. in: JCI | PubMed | Google Scholar

1Department of Medical Genetics, Kepler University Hospital, Johannes kepler University, Linz, Austria

2Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

3Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

4Department of Pediatrics, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

5Immunology Outpatient Clinic, Immunology Outpatient Clinic, Vienna, Austria

6Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University, Linz, Austria

7Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Me, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

8Faculty of Natural Sciences, Department of Molecular Biology, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

9Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

10Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria

Find articles by Soltysova, A. in: JCI | PubMed | Google Scholar

1Department of Medical Genetics, Kepler University Hospital, Johannes kepler University, Linz, Austria

2Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

3Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

4Department of Pediatrics, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

5Immunology Outpatient Clinic, Immunology Outpatient Clinic, Vienna, Austria

6Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University, Linz, Austria

7Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Me, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

8Faculty of Natural Sciences, Department of Molecular Biology, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

9Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

10Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria

Find articles by Yang, T. in: JCI | PubMed | Google Scholar

1Department of Medical Genetics, Kepler University Hospital, Johannes kepler University, Linz, Austria

2Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

3Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

4Department of Pediatrics, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

5Immunology Outpatient Clinic, Immunology Outpatient Clinic, Vienna, Austria

6Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University, Linz, Austria

7Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Me, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

8Faculty of Natural Sciences, Department of Molecular Biology, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

9Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

10Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria

Find articles by Feichtinger, R. in: JCI | PubMed | Google Scholar

1Department of Medical Genetics, Kepler University Hospital, Johannes kepler University, Linz, Austria

2Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

3Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

4Department of Pediatrics, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

5Immunology Outpatient Clinic, Immunology Outpatient Clinic, Vienna, Austria

6Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University, Linz, Austria

7Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Me, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

8Faculty of Natural Sciences, Department of Molecular Biology, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

9Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

10Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria

Find articles by Mayr, J. in: JCI | PubMed | Google Scholar |

1Department of Medical Genetics, Kepler University Hospital, Johannes kepler University, Linz, Austria

2Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

3Department of Pediatric Neurology, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

4Department of Pediatrics, Faculty of Medicine, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

5Immunology Outpatient Clinic, Immunology Outpatient Clinic, Vienna, Austria

6Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University, Linz, Austria

7Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Me, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

8Faculty of Natural Sciences, Department of Molecular Biology, Comenius University Bratislava and National Institute of Children's Diseases, Bratislava, Slovakia (Slovak Republic)

9Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, United States of America

10Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria

Find articles by Qi, L. in: JCI | PubMed | Google Scholar |

Published November 9, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI170882.
Copyright © 2023, Weis et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published November 9, 2023 - Version history
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Abstract

SEL1L-HRD1 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 bi-allelic SEL1L variant (p. Cys141Tyr) in five patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset 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 SEL1L-HRD1 ERAD complex in part via proteasomal-mediated self-destruction by HRD1. This study reports a new disease entity termed the “ENDI-agammaglobulinemia” (ENDI-A) syndrome and establishes an inverse correlation between SEL1L-HRD1 ERAD functionality and disease severity in humans.

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