دورية أكاديمية
أعرض في EDS

IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease.

التفاصيل البيبلوغرافية
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.)
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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
الوصف
تدمد:1432-1203
DOI:10.1007/s00439-021-02300-4