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Int J Mol Sci. 2019 Feb 15;20(4). pii: E835. doi: 10.3390/ijms20040835.

A Novel Rare Missense Variation of the NOD2 Gene: Evidencesof Implication in Crohn's Disease.

Author information

1
EA 2694-Santé Publique: épidémiologie et qualité des soins, University Lille, CHU Lille, F-59000 Lille, France. sara.frade@chru-lille.fr.
2
EA 7364-RADEME-Maladies RAres du Developpement embryonnaire et du MEtabolisme, University Lille, F-59000 Lille, France. Thomas.SMOL@chru-lille.fr.
3
CHU Lille, Institut de Génétique Médicale, F-59000 Lille, France. Thomas.SMOL@chru-lille.fr.
4
EA 7364-RADEME-Maladies RAres du Developpement embryonnaire et du MEtabolisme, University Lille, F-59000 Lille, France. Frederic.FRENOIS@chru-lille.fr.
5
CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, F-59000 Lille, France. Olivier.sand@cnrs.fr.
6
CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, F-59000 Lille, France. Emmanuel.Vaillant@cnrs.fr.
7
CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, F-59000 Lille, France. veronique.dhennin@cnrs.fr.
8
CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, F-59000 Lille, France. Amelie.bonnefond@cnrs.fr.
9
Department of Medicine, Section of Genomics of Common Disease, Imperial College London, London SW7 2AZ, UK. Amelie.bonnefond@cnrs.fr.
10
CNRS UMR 8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, University of Lille, F-59000 Lille, France. philippe.froguel@cnrs.fr.
11
Department of Medicine, Section of Genomics of Common Disease, Imperial College London, London SW7 2AZ, UK. philippe.froguel@cnrs.fr.
12
Registre Epimad, Gastroenterology Unit, Amiens University Hospital, F-80054 Amiens, France. fumery.mathurin@chu-amiens.fr.
13
Registre Epimad, Service de Santé Publique, d'Epidémiologie, d'Economie de la Santé et de la Prévention, Maison Régionale de la Recherche Clinique, CHU Lille, F-59000 Lille, France. nathalie.guillon@chru-lille.fr.
14
Inserm, UMR 995-LIRIC, Université de Lille, F-59000 Lille, France. nathalie.guillon@chru-lille.fr.
15
Registre Epimad, Service de Santé Publique, d'Epidémiologie, d'Economie de la Santé et de la Prévention, Maison Régionale de la Recherche Clinique, CHU Lille, F-59000 Lille, France. corinne.gower@chru-lille.fr.
16
Inserm, UMR 995-LIRIC, Université de Lille, F-59000 Lille, France. corinne.gower@chru-lille.fr.
17
EA 2694-Santé Publique: épidémiologie et qualité des soins, University Lille, CHU Lille, F-59000 Lille, France. francis.vasseur@univ-lille2.fr.

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.

KEYWORDS:

Crohn’s disease; NOD2 gene; WES; variation

PMID:
30769939
DOI:
10.3390/ijms20040835
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