Variants in STXBP3 are Associated with Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss and Immune Dysregulation-Reference-Cited by-同舟云学术

Variants in STXBP3 are Associated with Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss and Immune Dysregulation

Published:2021-04-23 Issue:11 Volume:15 Page:1908-1919
ISSN:1873-9946
Container-title:Journal of Crohn's and Colitis
language:en
Short-container-title:

Author:

Ouahed Jodie¹,Kelsen Judith R²,Spessott Waldo A³,Kooshesh Kameron⁴,Sanmillan Maria L³,Dawany Noor⁵,Sullivan Kathleen E⁶,Hamilton Kathryn E²,Slowik Voytek⁷,Nejentsev Sergey⁸⁹,Neves João Farela¹⁰¹¹,Flores Helena¹²,Chung Wendy K¹³,Wilson Ashley¹³,Anyane-Yeboa Kwame¹³,Wou Karen¹³,Jain Preti¹⁴¹⁵,Field Michael¹,Tollefson Sophia¹,Dent Maiah H¹⁶,Li Dalin¹⁷,Naito Takeo¹⁷,McGovern Dermot P B¹⁷,Kwong Andrew C¹¹⁸¹⁹,Taliaferro Faith¹¹⁹,Ordovas-Montanes Jose¹¹⁹²⁰²¹,Horwitz Bruce H¹²²,Kotlarz Daniel¹²³,Klein Christoph²³,Evans Jonathan²⁴,Dorsey Jill²⁴,Warner Neil²⁵²⁶,Elkadri Abdul²⁵²⁶,Muise Aleixo M²⁵²⁶^ORCID,Goldsmith Jeffrey²⁷,Thompson Benjamin²⁸,Engelhardt Karin R²⁸,Cant Andrew J²⁸²⁹,Hambleton Sophie²⁸²⁹,Barclay Andrew³⁰,Toth-Petroczy Agnes⁴³¹³²,Vuzman Dana⁴,Carmichael Nikkola⁴,Bodea Corneliu⁴,Cassa Christopher A⁴,Devoto Marcella³³³⁴³⁵,Maas Richard L⁴,Behrens Edward M³⁶,Giraudo Claudio G³,Snapper Scott B¹³⁷

Affiliation:

1. Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children’s Hospital, and Harvard Medical School, Boston, MA, 02115, USA

2. Division of Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

3. Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA

4. Brigham Genomic Medicine Program, Division of Genetics, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, 02115, USA

5. Department of Biomedical Health Informatics, The Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA

6. Division of Allergy and Immunology, The Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

7. Department of Medicine, Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

8. Division of Gastroenterology, Hepatology, and Nutrition, Children’s Mercy Kansas City, Kansas City, MO, 64108, USA

9. Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK

10. Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Centers, Amsterdam, the Netherlands

11. Primary Immunodeficiencies Unit; Hospital Dona Estefânia-CHLC, EPE, Lisbon, 1169, Portugal

12. CEDOC, Chronic Diseases Research Center, NOVA Medical School, Lisbon, 1150, Portugal

13. Gastroenterology Unit, Hospital Dona Estefânia-CHLC, EPE, Lisbon, 1169, Portugal

14. Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032, USA

15. Department of Medicine, Columbia University Medical Center, New York, NY, 10032, USA

16. Department of Genetics, Yale University, New Haven, CT, 06510, USA

17. F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA

18. Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115, USA

19. Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA

20. Program in Immunology, Harvard Medical School, Boston, MA, 02115, USA

21. Harvard Stem Cell Institute, Cambridge, MA, 02138, USA

22. Division of Emergency Medicine, Department of Pediatrics, Boston Children’s Hospital, and Harvard Medical School, Boston, MA, 02115, USA

23. Dr. von Hauner Children’s Hospital, Department of Pediatrics, University Hospital LMU Munich, Munich, 80337, Germany

24. Department of Pediatrics, Nemours Children’s Specialty Care, Jacksonville, FL 32207, USA

25. SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada

26. Department of Pediatrics and Biochemistry, University of Toronto, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada

27. Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, 02115, USA

28. Primary Immunodeficiency Group, III Theme, Institute of Cellular Medicine, Newcastle University, Newcastle, NE2 4HH, UK

29. Children’s Immunology Service, Great North Children’s Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, NE1 4LP, UK

30. Department of Paediatric Gastroenterology, Royal Hospital for Children, Glasgow, G51 4TF, UK

31. Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany

32. Center for Systems Biology Dresden, Dresden, Germany

33. Division of Human Genetics, The Children’s Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA

34. Department of Translational and Precision Medicine, University Sapienza, Rome 00185, Italy

35. CNR-IRGB, Cagliari 09042, Italy

36. Division of Rheumatology, The Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

37. Division of Gastroenterology, Department of Medicine, Brigham & Women’s Hospital and Harvard Medical School, Boston, MA, 02115, USA

Abstract

Abstract Background and Aims Very early onset inflammatory bowel disease [VEOIBD] is characterized by intestinal inflammation affecting infants and children less than 6 years of age. To date, over 60 monogenic aetiologies of VEOIBD have been identified, many characterized by highly penetrant recessive or dominant variants in underlying immune and/or epithelial pathways. We sought to identify the genetic cause of VEOIBD in a subset of patients with a unique clinical presentation. Methods Whole exome sequencing was performed on five families with ten patients who presented with a similar constellation of symptoms including medically refractory infantile-onset IBD, bilateral sensorineural hearing loss and, in the majority, recurrent infections. Genetic aetiologies of VEOIBD were assessed and Sanger sequencing was performed to confirm novel genetic findings. Western analysis on peripheral blood mononuclear cells and functional studies with epithelial cell lines were employed. Results In each of the ten patients, we identified damaging heterozygous or biallelic variants in the Syntaxin-Binding Protein 3 gene [STXBP3], a protein known to regulate intracellular vesicular trafficking in the syntaxin-binding protein family of molecules, but not associated to date with either VEOIBD or sensorineural hearing loss. These mutations interfere with either intron splicing or protein stability and lead to reduced STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity. Conclusion Overall, we describe a novel genetic syndrome and identify a critical role for STXBP3 in VEOIBD, sensorineural hearing loss and immune dysregulation.

Funder

Helmsley Charitable Trust

Boston Children's Hospital

National Institutes of Health

Institute for Translational Medicine and Therapeutics

Perelman School of Medicine

University of Pennsylvania

JPB Foundation

Sir Jules Thorn Charitable Trust

Wellcome Trust

Richard and Susan Smith Family Foundation

Damon Runyon Cancer Research Foundation