دورية أكاديمية
IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease.
العنوان: | IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease. |
---|---|
المؤلفون: | Cananzi M; Unit of Pediatric Gastroenterology, Digestive Endoscopy, Hepatology and Care of the Child with Liver Transplantation, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy. mara.cananzi@aopd.veneto.it., Wohler E; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, USA., Marzollo A; Pediatric Hematology, Oncology and Stem Cell Transplant Division, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy.; Istituto di Ricerca Pediatrica, Fondazione Città della Speranza, Padova, Italy., Colavito D; Research & Innovation (R&I Genetics) Srl, C.so Stati Uniti 4, Padova, Italy., You J; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, USA., Jing H; Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Bresolin S; Pediatric Hematology, Oncology and Stem Cell Transplant Division, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy.; Istituto di Ricerca Pediatrica, Fondazione Città della Speranza, Padova, Italy., Gaio P; Unit of Pediatric Gastroenterology, Digestive Endoscopy, Hepatology and Care of the Child with Liver Transplantation, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy., Martin R; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, USA., Mescoli C; Surgical Pathology and Cytopathology Unit, Department of Medicine (DIMED), University Hospital of Padova, Padova, Italy., Bade S; Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Posey JE; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA., Dalle Carbonare M; Research & Innovation (R&I Genetics) Srl, C.so Stati Uniti 4, Padova, Italy., Tung W; Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Jhangiani SN; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA., Bosa L; Unit of Pediatric Gastroenterology, Digestive Endoscopy, Hepatology and Care of the Child with Liver Transplantation, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy., Zhang Y; Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Filho JS; Division of Genetics, Department of Morphology and Genetics, Universidade Federal de Sao Paulo, Sao Paulo, Brazil., Gabelli M; Pediatric Hematology, Oncology and Stem Cell Transplant Division, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy., Kellermayer R; Section of Pediatric Gastroenterology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA., Kader HA; Department of Pediatrics, Division of Pediatric Gastroenterology & Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA., Oliva-Hemker M; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Perilongo G; Unit of Pediatric Gastroenterology, Digestive Endoscopy, Hepatology and Care of the Child with Liver Transplantation, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy., Lupski JR; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.; Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.; Texas Children's Hospital, Houston, Texas, USA., Biffi A; Pediatric Hematology, Oncology and Stem Cell Transplant Division, Department of Women's and Children's Health, University Hospital of Padova, Padova, Italy., Valle D; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, USA., Leon A; Research & Innovation (R&I Genetics) Srl, C.so Stati Uniti 4, Padova, Italy., de Macena Sobreira NL; McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, USA., Su HC; Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA., Guerrerio AL; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA. aguerrerio@jhmi.edu. |
المصدر: | Human genetics [Hum Genet] 2021 Sep; Vol. 140 (9), pp. 1299-1312. Date of Electronic Publication: 2021 Jun 29. |
نوع المنشور: | Clinical Trial; Journal Article |
اللغة: | English |
بيانات الدورية: | Publisher: Springer Verlag Country of Publication: Germany NLM ID: 7613873 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-1203 (Electronic) Linking ISSN: 03406717 NLM ISO Abbreviation: Hum Genet Subsets: MEDLINE |
أسماء مطبوعة: | Publication: Berlin : Springer Verlag Original Publication: Berlin, New York, Springer-Verlag. |
مواضيع طبية MeSH: | Loss of Function Mutation*, Inflammatory Bowel Diseases/*genetics , Interferon-Induced Helicase, IFIH1/*genetics, Child, Preschool ; Female ; Humans ; Infant ; Italy ; Male ; Whole Genome Sequencing |
مستخلص: | Genetic defects of innate immunity impairing intestinal bacterial sensing are linked to the development of Inflammatory Bowel Disease (IBD). Although much evidence supports a role of the intestinal virome in gut homeostasis, most studies focus on intestinal viral composition rather than on host intestinal viral sensitivity. To demonstrate the association between the development of Very Early Onset IBD (VEOIBD) and variants in the IFIH1 gene which encodes MDA5, a key cytosolic sensor for viral nucleic acids. Whole exome sequencing (WES) was performed in two independent cohorts of children with VEOIBD enrolled in Italy (n = 18) and USA (n = 24). Luciferase reporter assays were employed to assess MDA5 activity. An enrichment analysis was performed on IFIH1 comparing 42 VEOIBD probands with 1527 unrelated individuals without gastrointestinal or immunological issues. We identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD from a combined cohort of 42 children. One subject, carrying a homozygous truncating variant resulting in complete LoF, experienced neonatal-onset, pan-gastrointestinal, IBD-like enteropathy plus multiple infectious episodes. The remaining seven subjects, affected by VEOIBD without immunodeficiency, were carriers of one LoF variant in IFIH1. Among these, two patients also carried a second hypomorphic variant, with partial function apparent when MDA5 was weakly stimulated. Furthermore, IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p = 0.007). Complete and partial MDA5 deficiency is associated with VEOIBD with variable penetrance and expressivity, suggesting a role for impaired intestinal viral sensing in IBD pathogenesis. (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.) |
References: | Nature. 2017 Jul 13;547(7662):173-178. (PMID: 28658209) Inflamm Bowel Dis. 2016 Jan;22(1):202-12. (PMID: 26512716) J Immunol. 2011 Feb 1;186(3):1618-26. (PMID: 21187438) Immunity. 2013 May 23;38(5):855-69. (PMID: 23706667) J Virol. 2019 Nov 13;93(23):. (PMID: 31511389) Genome Med. 2015 Jul 30;7(1):81. (PMID: 26229552) Nature. 2001 May 31;411(6837):599-603. (PMID: 11385576) Front Med (Lausanne). 2018 Feb 19;5:32. (PMID: 29515999) J Virol. 2010 Nov;84(21):11350-8. (PMID: 20739519) Front Immunol. 2018 Jan 30;9:72. (PMID: 29441063) Mol Cell. 2021 Feb 4;81(3):599-613.e8. (PMID: 33373584) Trends Microbiol. 2019 Jan;27(1):75-85. (PMID: 30201512) J Comput Biol. 2004;11(2-3):377-94. (PMID: 15285897) Immunol Lett. 2009 Mar 24;123(1):9-13. (PMID: 19201382) Genet Epidemiol. 2013 Jan;37(1):110-21. (PMID: 23032573) Nat Methods. 2016 Feb;13(2):109-10. (PMID: 26820543) Front Genet. 2017 Sep 22;8:130. (PMID: 29018476) Mol Ther. 2017 Sep 6;25(9):2093-2103. (PMID: 28760668) Genome Res. 2010 Sep;20(9):1297-303. (PMID: 20644199) BMC Bioinformatics. 2014 Jan 29;15:30. (PMID: 24475911) Front Immunol. 2017 Jun 30;8:749. (PMID: 28713375) Inflamm Bowel Dis. 2011 Sep;17(9):1943-54. (PMID: 21830273) Cell Res. 2007 Oct;17(10):858-68. (PMID: 17893708) Nat Genet. 2014 May;46(5):503-509. (PMID: 24686847) Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):17390-5. (PMID: 21960441) Inflamm Bowel Dis. 2011 Jun;17(6):1314-21. (PMID: 21560194) Immunol Rev. 2019 Jan;287(1):162-185. (PMID: 30565237) Proc Natl Acad Sci U S A. 2017 Aug 1;114(31):8342-8347. (PMID: 28716935) Exp Mol Med. 2019 Dec 11;51(12):1-13. (PMID: 31827068) Nat Immunol. 2017 Oct;18(10):1084-1093. (PMID: 28846084) Nat Immunol. 2017 Jul;18(7):744-752. (PMID: 28553952) BMC Bioinformatics. 2010 Nov 08;11:548. (PMID: 21059217) Gut. 2013 Dec;62(12):1795-805. (PMID: 24203055) Nat Genet. 2011 May;43(5):491-8. (PMID: 21478889) Gut. 2015 Jan;64(1):66-76. (PMID: 24572142) BMC Genomics. 2014 Apr 03;15:256. (PMID: 24694260) Cell. 2013 Jan 17;152(1-2):276-89. (PMID: 23273991) J Exp Clin Cancer Res. 2017 Jan 5;36(1):2. (PMID: 28057020) Genome Med. 2013 Jun 27;5(6):57. (PMID: 23806086) Nucleic Acids Res. 2001 Mar 1;29(5):1185-90. (PMID: 11222768) Science. 2015 Apr 24;348(6233):448-53. (PMID: 25814066) Genome Biol. 2011 Jul 25;12(7):R68. (PMID: 21787409) J Exp Med. 2017 Jul 3;214(7):1949-1972. (PMID: 28606988) J Comput Biol. 1997 Fall;4(3):311-23. (PMID: 9278062) Cell Mol Gastroenterol Hepatol. 2015 Sep 1;1(5):462-476. (PMID: 26393237) J Pediatr Gastroenterol Nutr. 2014 Jun;58(6):795-806. (PMID: 24231644) Gastroenterology. 2016 May;150(5):1196-1207. (PMID: 26836588) J Virol. 2018 Nov 12;92(23):. (PMID: 30209176) Gut. 2017 Jun;66(6):1060-1073. (PMID: 26953272) Nat Genet. 2006 Jun;38(6):617-9. (PMID: 16699517) Am J Hum Genet. 2015 Feb 5;96(2):275-82. (PMID: 25620204) EMBO Mol Med. 2018 Apr;10(4):. (PMID: 29567797) Sci Transl Med. 2017 Apr 19;9(386):. (PMID: 28424327) Cell. 2017 Feb 23;168(5):789-800.e10. (PMID: 28235196) Medicine (Baltimore). 2010 Nov;89(6):403-425. (PMID: 21057262) Cell Mol Life Sci. 2017 Jul;74(13):2395-2411. (PMID: 28224203) Int Rev Immunol. 2017 Mar 4;36(2):74-88. (PMID: 28333574) Front Immunol. 2019 Jul 17;10:1586. (PMID: 31379819) Nat Rev Gastroenterol Hepatol. 2014 Feb;11(2):88-98. (PMID: 24345891) Arthritis Rheumatol. 2015 Jun;67(6):1592-7. (PMID: 25777993) Mucosal Immunol. 2018 Mar;11(2):562-574. (PMID: 29091079) J Neuroimmunol. 2009 Jul 25;212(1-2):125-31. (PMID: 19450885) Hum Mutat. 2015 Apr;36(4):425-31. (PMID: 25684268) Bioinformatics. 2009 Aug 15;25(16):2078-9. (PMID: 19505943) Am J Hum Genet. 2018 Aug 2;103(2):171-187. (PMID: 30032986) Inflamm Bowel Dis. 2021 Feb 16;27(3):295-302. (PMID: 32386060) Cell Res. 2007 Dec;17(12):974-5. (PMID: 18075517) Nat Genet. 2016 May;48(5):510-8. (PMID: 26974007) Proc Natl Acad Sci U S A. 2015 Nov 3;112(44):13615-20. (PMID: 26483451) Trends Pharmacol Sci. 2019 Feb;40(2):116-127. (PMID: 30606502) Nat Rev Immunol. 2020 Sep;20(9):537-551. (PMID: 32203325) |
معلومات مُعتمدة: | UM1 HG006542 United States HG NHGRI NIH HHS; ZIA AI001059 United States ImNIH Intramural NIH HHS |
المشرفين على المادة: | EC 3.6.1.- (IFIH1 protein, human) EC 3.6.4.13 (Interferon-Induced Helicase, IFIH1) |
تواريخ الأحداث: | Date Created: 20210629 Date Completed: 20210809 Latest Revision: 20240216 |
رمز التحديث: | 20240216 |
مُعرف محوري في PubMed: | PMC8423350 |
DOI: | 10.1007/s00439-021-02300-4 |
PMID: | 34185153 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1432-1203 |
---|---|
DOI: | 10.1007/s00439-021-02300-4 |