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

Autor: Ouahed J; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA., Kelsen JR; Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Spessott WA; Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA., Kooshesh K; Brigham Genomic Medicine Program, Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA., Sanmillan ML; Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA., Dawany N; Department of Biomedical Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA., Sullivan KE; Division of Allergy and Immunology, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Hamilton KE; Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Slowik V; Department of Medicine, Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Nejentsev S; Division of Gastroenterology, Hepatology, and Nutrition, Children's Mercy Kansas City, Kansas City, MO, 64108, USA.; Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK., Neves JF; Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Centers, Amsterdam, the Netherlands.; Primary Immunodeficiencies Unit; Hospital Dona Estefânia-CHLC, EPE, Lisbon, 1169, Portugal., Flores H; CEDOC, Chronic Diseases Research Center, NOVA Medical School, Lisbon, 1150, Portugal., Chung WK; Gastroenterology Unit, Hospital Dona Estefânia-CHLC, EPE, Lisbon, 1169, Portugal., Wilson A; Gastroenterology Unit, Hospital Dona Estefânia-CHLC, EPE, Lisbon, 1169, Portugal., Anyane-Yeboa K; Gastroenterology Unit, Hospital Dona Estefânia-CHLC, EPE, Lisbon, 1169, Portugal., Wou K; Gastroenterology Unit, Hospital Dona Estefânia-CHLC, EPE, Lisbon, 1169, Portugal., Jain P; Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032, USA.; Department of Medicine, Columbia University Medical Center, New York, NY, 10032, USA., Field M; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA., Tollefson S; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA., Dent MH; Department of Genetics, Yale University, New Haven, CT, 06510, USA., Li D; F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA., Naito T; F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA., McGovern DPB; F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA., Kwong AC; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA.; Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Taliaferro F; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Ordovas-Montanes J; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA.; Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.; Program in Immunology, Harvard Medical School, Boston, MA, 02115, USA.; Harvard Stem Cell Institute, Cambridge, MA, 02138, USA., Horwitz BH; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA.; Division of Emergency Medicine, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA., Kotlarz D; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA.; Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital LMU Munich, Munich, 80337, Germany., Klein C; Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital LMU Munich, Munich, 80337, Germany., Evans J; Department of Pediatrics, Nemours Children's Specialty Care, Jacksonville, FL 32207, USA., Dorsey J; Department of Pediatrics, Nemours Children's Specialty Care, Jacksonville, FL 32207, USA., Warner N; SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada.; Department of Pediatrics and Biochemistry, University of Toronto, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada., Elkadri A; SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada.; Department of Pediatrics and Biochemistry, University of Toronto, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada., Muise AM; SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada.; Department of Pediatrics and Biochemistry, University of Toronto, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada., Goldsmith J; Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA., Thompson B; Primary Immunodeficiency Group, III Theme, Institute of Cellular Medicine, Newcastle University, Newcastle, NE2 4HH, UK., Engelhardt KR; Primary Immunodeficiency Group, III Theme, Institute of Cellular Medicine, Newcastle University, Newcastle, NE2 4HH, UK., Cant AJ; Primary Immunodeficiency Group, III Theme, Institute of Cellular Medicine, Newcastle University, Newcastle, NE2 4HH, UK.; Children's Immunology Service, Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, NE1 4LP, UK., Hambleton S; Primary Immunodeficiency Group, III Theme, Institute of Cellular Medicine, Newcastle University, Newcastle, NE2 4HH, UK.; Children's Immunology Service, Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, NE1 4LP, UK., Barclay A; Department of Paediatric Gastroenterology, Royal Hospital for Children, Glasgow, G51 4TF, UK., Toth-Petroczy A; Brigham Genomic Medicine Program, Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.; Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.; Center for Systems Biology Dresden, Dresden, Germany., Vuzman D; Brigham Genomic Medicine Program, Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA., Carmichael N; Brigham Genomic Medicine Program, Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA., Bodea C; Brigham Genomic Medicine Program, Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA., Cassa CA; Brigham Genomic Medicine Program, Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA., Devoto M; Division of Human Genetics, The Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.; Department of Translational and Precision Medicine, University Sapienza, Rome 00185, Italy.; CNR-IRGB, Cagliari 09042, Italy., Maas RL; Brigham Genomic Medicine Program, Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA., Behrens EM; Division of Rheumatology, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA., Giraudo CG; Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA., Snapper SB; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA.; Division of Gastroenterology, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
Jazyk: angličtina
Zdroj: Journal of Crohn's & colitis [J Crohns Colitis] 2021 Nov 08; Vol. 15 (11), pp. 1908-1919.
DOI: 10.1093/ecco-jcc/jjab077
Abstrakt: 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.
(© The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Databáze: MEDLINE
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