EA 2694-Santé Publique: épidémiologie et qualité des soins, University Lille, CHU Lille, F-59000 Lille, France.
EA 7364-RADEME-Maladies RAres du Developpement embryonnaire et du MEtabolisme, University Lille, F-59000 Lille, France.
Int J Mol Sci. 2019 Feb 15;20(4):835. doi: 10.3390/ijms20040835.
The 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 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 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 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.
该基因参与了对细菌肽聚糖的先天免疫反应，与克罗恩病（CD）密切相关，其优势比范围为 3⁻36。有三个或更多 CD 受影响成员的家族与基因变异的高频率有关，例如 R702W、G908R 和 1007fs，并在 EPIMAD 登记处报告。然而，一些罕见的 CD 多态性家族被描述为没有鉴定到与疾病相关的常见基因变异。为了确定与 CD 密切相关的新遗传变异，对可用的受试者进行了全外显子组测序，这些受试者包括两代中患有克罗恩病且无 R702W 和 G908R 变异的四名患者和三名无相关的相关受试者。检测到一种罕见的、尚未报道的基因 N1010K 错义变异，并在受影响的患者中发生共分离。计算评估和建模表明，N1010K 变异与 CD 具有不利影响。此外，对 N1010K 和 1007fs 作为两个更严重的 CD 家族成员的复合杂合状态的累积特征强烈表明，N1010K 可能是参与克罗恩病遗传易感性的新风险因素。
