Exome sequencing identifies a novel FOXP3 mutation in a 2-generation family with inflammatory bowel disease.
Exome sequencing identifies a novel FOXP3 mutation in a 2-generation family with inflammatory bowel disease.
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DOI：
10.1097/mpg.0000000000000302
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发表时间：
2014-05
影响因子：
2.9
通讯作者：
Kugathasan S
中科院分区：
文献类型：
--
作者：
Okou DT;Mondal K;Faubion WA;Kobrynski LJ;Denson LA;Mulle JG;Ramachandran D;Xiong Y;Svingen P;Patel V;Bose P;Waters JP;Prahalad S;Cutler DJ;Zwick ME;Kugathasan S
炎症性肠病 (IBD) 具有遗传性，但与 IBD 发病机制相关的 163 种变异仅占遗传性的 25%。罕见的、高渗透性的遗传变异也可以解释孟德尔形式的 IBD 和一些缺失的遗传性。为了验证罕见的功能丧失突变可能是致病因素的假设，我们对一个欧洲血统两代家族的 5 名患有早发性非典型 IBD 的成员进行了全外显子组测序 (WES)。对所有 5 名家庭成员进行了 WES；母亲和 3 个雄性后代受到影响，而父亲则未受影响。使用映射、注释和过滤标准来减少候选变体。对于功能测试，我们进行了叉头盒 P3 (FOXP3) 染色和 T 细胞抑制测定。我们在 X 连锁 FOXP3 基因的外显子 6 中发现了一个新的错义变异。 FOXP3 中的 c.694A>C 取代导致蛋白质位置 232 处的半胱氨酸-联甘氨酸发生变化，这种变化在所有脊椎动物中都是完全保守的。这种变异（母亲为杂合子，所有 3 个受影响的儿子为半合子）不会损害 FOXP3 蛋白表达，但显着降低宿主 T 调节细胞抑制不适当的自身免疫反应的能力。该变异导致较轻微的免疫失调、多内分泌病、肠病和早发性 IBD 的 X 连锁表型。我们的研究展示了 WES 的成功应用，对具有非典型 IBD 样表型的多重受影响家庭进行明确的分子诊断。我们的结果对于疾病生物学和疾病导向的治疗开发也具有重要意义。
Inflammatory bowel disease (IBD) is heritable, but a total of 163 variants commonly implicated in IBD pathogenesis account for only 25% of the heritability. Rare, highly penetrant genetic variants may also explain mendelian forms of IBD and some of the missing heritability. To test the hypothesis that rare loss-of-function mutations can be causative, we performed whole exome sequencing (WES) on 5 members of a 2-generation family of European ancestry presenting with an early-onset and atypical form of IBD. WES was performed for all of the 5 family members; the mother and 3 male offspring were affected, whereas the father was unaffected. Mapping, annotation, and filtering criteria were used to reduce candidate variants. For functional testing we performed forkhead box P3 (FOXP3) staining and a T-cell suppression assay. We identified a novel missense variant in exon 6 of the X-linked FOXP3 gene. The c.694A>C substitution in FOXP3 results in a cysteine-toglycine change at the protein position 232 that is completely conserved among all vertebrates. This variant (heterozygous in the mother and hemizygous in all 3 affected sons) did not impair FOXP3 protein expression, but significantly reduced the ability of the host's T regulatory cells to suppress an inappropriate autoimmune response. The variant results in a milder immune dysregulation, polyendocrinopathy, enteropathy, and X-linked phenotype with early-onset IBD. Our study illustrates the successful application of WES for making a definitive molecular diagnosis in a case of multiply affected families, with atypical IBD-like phenotype. Our results also have important implications for disease biology and disease-directed therapeutic development.