Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

A Novel Rare Missense Variation of the NOD2 Gene: Evidences of Implication in Crohn’s Disease

Sara Frade-Proud’hon-Clerc
* ,
Thomas Smol
ORCID logo ,
Frederic Frenois
,
Olivier Sand
,
Emmanuel Vaillant
,
Véronique Dhennin
,
Amélie Bonnefond
,
Philippe Frouguel
,
Mathurin Fumery
,
Nathalie Guillon-Dellac
,
Corinne Gower-Rousseau
,
Francis Vasseur
Version 1 : Received: 12 November 2018 / Approved: 20 November 2018 / Online: 20 November 2018 (08:44:01 CET)

A peer-reviewed article of this Preprint also exists.

Frade-Proud’Hon-Clerc, S.; Smol, T.; Frenois, F.; Sand, O.; Vaillant, E.; Dhennin, V.; Bonnefond, A.; Froguel, P.; Fumery, M.; Guillon-Dellac, N.; Gower-Rousseau, C.; Vasseur, F. A Novel Rare Missense Variation of the NOD2 Gene: Evidencesof Implication in Crohn’s Disease. Int. J. Mol. Sci. 2019, 20, 835. Frade-Proud’Hon-Clerc, S.; Smol, T.; Frenois, F.; Sand, O.; Vaillant, E.; Dhennin, V.; Bonnefond, A.; Froguel, P.; Fumery, M.; Guillon-Dellac, N.; Gower-Rousseau, C.; Vasseur, F. A Novel Rare Missense Variation of the NOD2 Gene: Evidencesof Implication in Crohn’s Disease. Int. J. Mol. Sci. 2019, 20, 835.

Abstract

The NOD2 gene, involved in innate immune responses to bacterial peptidoglycan, has been found to be strongly associated with Crohn’s Disease, with an Odd Ratio ranging from 3 to 36. Families with 3 or more CD affected patients were related to high frequency of NOD2 gene variations as R702W, G908R, 1007fs and were reported in 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) with a major effect on Crohn’s disease (CD), whole exome sequencing was performed in available subjects comprising 4 patients on 2 generations affected with Crohn’s disease without R702W and G908R variation, and 3 unaffected related subjects. A new rare and not yet reported missense variation of the NOD2 gene, the N1010K, was detected and co-segregated across affected patients. In silico evaluation and modeling highlighted evidences for a deleterious effect of the N1010K variation regarding CD. Moreover cumulative characterization of N1010K and 1007fs as compound heterozygous state in two more severely CD family members strongly suggesting that the N1010K should be a new risk factor involved in Crohn’s disease genetic susceptibility.

Keywords

Crohn’s disease; NOD2 gene; variation; WES.

Subject

Medicine and Pharmacology, Gastroenterology and Hepatology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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