Advertisement

ResearchIn-Press PreviewCell biology Open Access | 10.1172/JCI170054

Hypomorphic variants of SEL1L-HRD1 ER-associated degradation are associated with neurodevelopmental disorders

Huilun Helen Wang,1 Liangguang Leo Lin,1 Zexin Jason Li,1 Xiaoqiong Wei,1 Omar Askander,2 Gerarda Cappuccio,3 Mais O. Hashem,4 Laurence Hubert,5 Arnold Munnich,5 Mashael Alqahtani,4 Qi Pang,6 Margit Burmeister,7 You Lu,8 Karine Poirier,5 Claude Besmond,5 Shengyi Sun,1 Nicola Brunetti-Pierri,3 Fowzan S. Alkuraya,9 and Ling Qi1

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Hopital Cheik Zaïd, Hopital Universitaire International, Rabat, Morocco

3Department of Translational Medicine, University of Naples, Naples, Italy

4Department of Translational Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

5Imagine Institute, Inserm UMR1163, Paris, France

6Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, China

7Department of Human Genetics, The University of Michigan, Ann Arbor, United States of America

8Life Sciences Institute, The University of Michigan Medical School, Ann Arbor, United States of America

9King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Hopital Cheik Zaïd, Hopital Universitaire International, Rabat, Morocco

3Department of Translational Medicine, University of Naples, Naples, Italy

4Department of Translational Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

5Imagine Institute, Inserm UMR1163, Paris, France

6Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, China

7Department of Human Genetics, The University of Michigan, Ann Arbor, United States of America

8Life Sciences Institute, The University of Michigan Medical School, Ann Arbor, United States of America

9King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Hopital Cheik Zaïd, Hopital Universitaire International, Rabat, Morocco

3Department of Translational Medicine, University of Naples, Naples, Italy

4Department of Translational Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

5Imagine Institute, Inserm UMR1163, Paris, France

6Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, China

7Department of Human Genetics, The University of Michigan, Ann Arbor, United States of America

8Life Sciences Institute, The University of Michigan Medical School, Ann Arbor, United States of America

9King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Hopital Cheik Zaïd, Hopital Universitaire International, Rabat, Morocco

3Department of Translational Medicine, University of Naples, Naples, Italy

4Department of Translational Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

5Imagine Institute, Inserm UMR1163, Paris, France

6Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, China

7Department of Human Genetics, The University of Michigan, Ann Arbor, United States of America

8Life Sciences Institute, The University of Michigan Medical School, Ann Arbor, United States of America

9King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Hopital Cheik Zaïd, Hopital Universitaire International, Rabat, Morocco

3Department of Translational Medicine, University of Naples, Naples, Italy

4Department of Translational Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

5Imagine Institute, Inserm UMR1163, Paris, France

6Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, China

7Department of Human Genetics, The University of Michigan, Ann Arbor, United States of America

8Life Sciences Institute, The University of Michigan Medical School, Ann Arbor, United States of America

9King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

Find articles by Askander, O. in: JCI | PubMed | Google Scholar

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Hopital Cheik Zaïd, Hopital Universitaire International, Rabat, Morocco

3Department of Translational Medicine, University of Naples, Naples, Italy

4Department of Translational Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

5Imagine Institute, Inserm UMR1163, Paris, France

6Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, China

7Department of Human Genetics, The University of Michigan, Ann Arbor, United States of America

8Life Sciences Institute, The University of Michigan Medical School, Ann Arbor, United States of America

9King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Hopital Cheik Zaïd, Hopital Universitaire International, Rabat, Morocco

3Department of Translational Medicine, University of Naples, Naples, Italy

4Department of Translational Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

5Imagine Institute, Inserm UMR1163, Paris, France

6Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, China

7Department of Human Genetics, The University of Michigan, Ann Arbor, United States of America

8Life Sciences Institute, The University of Michigan Medical School, Ann Arbor, United States of America

9King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

Find articles by Hashem, M. in: JCI | PubMed | Google Scholar

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Hopital Cheik Zaïd, Hopital Universitaire International, Rabat, Morocco

3Department of Translational Medicine, University of Naples, Naples, Italy

4Department of Translational Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

5Imagine Institute, Inserm UMR1163, Paris, France

6Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, China

7Department of Human Genetics, The University of Michigan, Ann Arbor, United States of America

8Life Sciences Institute, The University of Michigan Medical School, Ann Arbor, United States of America

9King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Hopital Cheik Zaïd, Hopital Universitaire International, Rabat, Morocco

3Department of Translational Medicine, University of Naples, Naples, Italy

4Department of Translational Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

5Imagine Institute, Inserm UMR1163, Paris, France

6Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, China

7Department of Human Genetics, The University of Michigan, Ann Arbor, United States of America

8Life Sciences Institute, The University of Michigan Medical School, Ann Arbor, United States of America

9King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Hopital Cheik Zaïd, Hopital Universitaire International, Rabat, Morocco

3Department of Translational Medicine, University of Naples, Naples, Italy

4Department of Translational Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

5Imagine Institute, Inserm UMR1163, Paris, France

6Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, China

7Department of Human Genetics, The University of Michigan, Ann Arbor, United States of America

8Life Sciences Institute, The University of Michigan Medical School, Ann Arbor, United States of America

9King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

Find articles by Alqahtani, M. in: JCI | PubMed | Google Scholar |

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Hopital Cheik Zaïd, Hopital Universitaire International, Rabat, Morocco

3Department of Translational Medicine, University of Naples, Naples, Italy

4Department of Translational Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

5Imagine Institute, Inserm UMR1163, Paris, France

6Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, China

7Department of Human Genetics, The University of Michigan, Ann Arbor, United States of America

8Life Sciences Institute, The University of Michigan Medical School, Ann Arbor, United States of America

9King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

Find articles by Pang, Q. in: JCI | PubMed | Google Scholar

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Hopital Cheik Zaïd, Hopital Universitaire International, Rabat, Morocco

3Department of Translational Medicine, University of Naples, Naples, Italy

4Department of Translational Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

5Imagine Institute, Inserm UMR1163, Paris, France

6Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, China

7Department of Human Genetics, The University of Michigan, Ann Arbor, United States of America

8Life Sciences Institute, The University of Michigan Medical School, Ann Arbor, United States of America

9King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

Find articles by Burmeister, M. in: JCI | PubMed | Google Scholar |

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Hopital Cheik Zaïd, Hopital Universitaire International, Rabat, Morocco

3Department of Translational Medicine, University of Naples, Naples, Italy

4Department of Translational Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

5Imagine Institute, Inserm UMR1163, Paris, France

6Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, China

7Department of Human Genetics, The University of Michigan, Ann Arbor, United States of America

8Life Sciences Institute, The University of Michigan Medical School, Ann Arbor, United States of America

9King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

Find articles by Lu, Y. in: JCI | PubMed | Google Scholar |

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Hopital Cheik Zaïd, Hopital Universitaire International, Rabat, Morocco

3Department of Translational Medicine, University of Naples, Naples, Italy

4Department of Translational Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

5Imagine Institute, Inserm UMR1163, Paris, France

6Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, China

7Department of Human Genetics, The University of Michigan, Ann Arbor, United States of America

8Life Sciences Institute, The University of Michigan Medical School, Ann Arbor, United States of America

9King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Hopital Cheik Zaïd, Hopital Universitaire International, Rabat, Morocco

3Department of Translational Medicine, University of Naples, Naples, Italy

4Department of Translational Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

5Imagine Institute, Inserm UMR1163, Paris, France

6Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, China

7Department of Human Genetics, The University of Michigan, Ann Arbor, United States of America

8Life Sciences Institute, The University of Michigan Medical School, Ann Arbor, United States of America

9King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

Find articles by Besmond, C. in: JCI | PubMed | Google Scholar |

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Hopital Cheik Zaïd, Hopital Universitaire International, Rabat, Morocco

3Department of Translational Medicine, University of Naples, Naples, Italy

4Department of Translational Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

5Imagine Institute, Inserm UMR1163, Paris, France

6Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, China

7Department of Human Genetics, The University of Michigan, Ann Arbor, United States of America

8Life Sciences Institute, The University of Michigan Medical School, Ann Arbor, United States of America

9King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Hopital Cheik Zaïd, Hopital Universitaire International, Rabat, Morocco

3Department of Translational Medicine, University of Naples, Naples, Italy

4Department of Translational Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

5Imagine Institute, Inserm UMR1163, Paris, France

6Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, China

7Department of Human Genetics, The University of Michigan, Ann Arbor, United States of America

8Life Sciences Institute, The University of Michigan Medical School, Ann Arbor, United States of America

9King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

Find articles by Brunetti-Pierri, N. in: JCI | PubMed | Google Scholar |

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Hopital Cheik Zaïd, Hopital Universitaire International, Rabat, Morocco

3Department of Translational Medicine, University of Naples, Naples, Italy

4Department of Translational Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

5Imagine Institute, Inserm UMR1163, Paris, France

6Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, China

7Department of Human Genetics, The University of Michigan, Ann Arbor, United States of America

8Life Sciences Institute, The University of Michigan Medical School, Ann Arbor, United States of America

9King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

Find articles by Alkuraya, F. in: JCI | PubMed | Google Scholar |

1Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, United States of America

2Hopital Cheik Zaïd, Hopital Universitaire International, Rabat, Morocco

3Department of Translational Medicine, University of Naples, Naples, Italy

4Department of Translational Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

5Imagine Institute, Inserm UMR1163, Paris, France

6Department of Neurosurgery, Provincial Hospital Affiliated to Shandong University, Jinan, China

7Department of Human Genetics, The University of Michigan, Ann Arbor, United States of America

8Life Sciences Institute, The University of Michigan Medical School, Ann Arbor, United States of America

9King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

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

Published November 9, 2023 - More info

J Clin Invest. https://doi.org/10.1172/JCI170054.
Copyright © 2023, Wang 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
View PDF
Abstract

Recent studies using cell type-specific knockout mouse models have improved our understanding of the pathophysiological relevance of SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD); however, its importance in humans remains unclear as no disease variant has been identified. Here we report the identification of three bi-allelic missense variants of SEL1L and HRD1 (or SYVN1) in six children from three independent families presenting with developmental delay, intellectual disability, microcephaly, facial dysmorphisms, hypotonia and/or ataxia. These SEL1L (p.Gly585Asp, p.Met528Arg) and HRD1 (p.Pro398Leu) variants were hypomorphic and impaired ERAD function at distinct steps of ERAD including substrate recruitment (SEL1L p.Gly585Asp), SEL1L-HRD1 complex formation (SEL1L p.Met528Arg), and HRD1 activity (HRD1 p.Pro398Leu). Our study not only provide new insights into the structure-function relationship of SEL1L-HRD1 ERAD, but also establish the importance of SEL1L-HRD1 ERAD in humans.

Graphical Abstract
graphical abstract
Supplemental material

View Supplemental Video 1. Patient 1 carrying SEL1L p.G585D variant at 13 years of age. Video shows the patient walking with clumsy gait and clenching fists stiffly besides the body.

View Supplemental Video 2. Patient 2 carrying SEL1L p.M528R variant at 17 years of age. Video shows the patient walking with wide-based gait, balancing with hand support, hypotonia and ataxia.

View Supplemental Video 3. Patient 6 carrying HRD1 p.P398L variant at 21 years of age. Video shows the patient walking and climbing the stairs. The patient also shows stereotypies with repetitive, purposeless hand movements.

View

Version history
  • Version 1 (November 9, 2023): In-Press Preview
Advertisement
Advertisement