1. A Novel Rare Missense Variation of the NOD2 Gene: Evidences of Implication in Crohn’s Disease
- Author
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Frade-Proud'hon-Clerc, Sara, Smol, Thomas, Frenois, Frederic, Sand, Olivier, Vaillant, Emmanuel, Dhennin, Veronique, Bonnefond, Amelie, Froguel, Philippe, Fumery, Mathurin, Guillon-Dellac, Nathalie, Gower, Corinne, Vasseur, Francis, Evaluation des technologies de santé et des pratiques médicales - ULR 2694 (METRICS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille, Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 (RADEME), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Génétique Médicale [CHRU Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (GI3M), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Imperial College London, CHU Amiens-Picardie, Registre EPIMAD, CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-CHU Amiens-Picardie-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Lille Inflammation Research International Center - U 995 (LIRIC), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Maison Régionale de la Recherche Clinique [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), This research was funded by the Association de l’Etude des Anomalies Congénitales (AEAC)., We would like to thank Nigel Quayle for kindly correcting the manuscript. This work is issued from the Epimad registry, EPIMAD is supported by the Institut National de la Santé et de la Recherche Médicale (INSERM) and the Agence Santé Publique France and also received logistic support from the European Charity Fundation DigestScience (Lille, France). We would also like to thank the patients and their family, who have kindly contributed to this study, Metabolic functional (epi)genomics and molecular mechanisms involved in type 2 diabetes and related diseases - UMR 8199 - UMR 1283 (EGENODIA (GI3M)), and Université de Lille, LillOA
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Crohn’s disease ,Adult ,Male ,Heterozygote ,Adolescent ,Genotype ,Protein Conformation ,Mutation, Missense ,Nod2 Signaling Adaptor Protein ,NOD2 gene ,Peptidoglycan ,[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics ,Polymorphism, Single Nucleotide ,Article ,Crohn''s disease ,lcsh:Chemistry ,Crohn Disease ,Exome Sequencing ,Humans ,Genetic Predisposition to Disease ,Child ,lcsh:QH301-705.5 ,Alleles ,Genetic Association Studies ,[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology ,digestive system diseases ,Immunity, Innate ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,lcsh:Biology (General) ,lcsh:QD1-999 ,Mutation ,WES ,Female ,variation - Abstract
The NOD2 gene, involved in innate immune responses to bacterial peptidoglycan, has been found to be closely associated with Crohn’s Disease (CD), with an Odds Ratio ranging from 3⁻36. Families with three or more CD-affected members were related to a high frequency of NOD2 gene variations, such as R702W, G908R, and 1007fs, and were reported in the EPIMAD Registry. However, some rare CD multiplex families were described without identification of common NOD2 linked-to-disease variations. In order to identify new genetic variation(s) closely linked with CD, whole exome sequencing was performed on available subjects, comprising four patients in two generations affected with Crohn’s disease without R702W and G908R variation and three unaffected related subjects. A rare and, not yet, reported missense variation of the NOD2 gene, N1010K, was detected and co-segregated across affected patients. In silico evaluation and modelling highlighted evidence for an adverse effect of the N1010K variation with regard to CD. Moreover, cumulative characterization of N1010K and 1007fs as a compound heterozygous state in two, more severe CD family members strongly suggests that N1010K could well be a new risk factor involved in Crohn’s disease genetic susceptibility.
- Published
- 2019
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