Jung Eun Suk, Petersen Britt-Sabina, Mayr Gabriele, Cheon Jae Hee, Kang Yunkoo, Lee Seok Joo, Che Xiumei, Kim Won Ho, Kim Seung, Schreiber Stefan, Franke Andre, Koh Hong
Departments of Internal Medicine and Institute of Gastroenterology.
Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
Eur J Gastroenterol Hepatol. 2018 Dec;30(12):1491-1496. doi: 10.1097/MEG.0000000000001247.
Inflammatory bowel diseases (IBDs) are chronic and multifactorial diseases resulting from a complex interaction of host genetic factors and environmental stimuli. Although many genome-wide association studies have identified host genetic factors associated with IBD, rare Mendelian forms of IBD have been reported in patients with very early onset forms. Therefore, this study aimed to identify genetic variants associated with infantile-onset IBD.
We obtained genomic DNA from whole blood samples of a male patient with infantile-onset IBD and nonconsanguineous Korean parents. Whole-exome sequencing was performed using trio samples. Then, we analyzed the data using susceptibility genes for monogenic forms of IBD and various immunodeficiencies and protein structural analysis.
The patient who presented with oral aphthous ulcers at the age of 14 days suffered from severe colitis and was refractory to medical treatment. Compound heterozygous mutations in IL10RA (p.R101W; p.T179T) were found in the patient. In addition, a hemizygous mutation in complement factor properdin (CFP) (p.L456V) located on the X-chromosome was detected, inherited from the patient's mother. Protein structural modeling suggested impaired properdin subunit interactions by p.L456V that may hamper protein oligomerization required for complement activation.
This study identified compound heterozygous mutations in IL10RA combined with a hemizygous CFP mutation in infantile-onset IBD by using whole-exome sequencing. CFP p.L456V may exacerbate symptoms of infantile-onset IBD by disturbing oligomerization of properdin.
炎症性肠病（IBD）是由宿主遗传因素和环境刺激复杂相互作用导致的慢性多因素疾病。尽管许多全基因组关联研究已经确定了与IBD相关的宿主遗传因素，但在极早发型IBD患者中也报道了罕见的孟德尔形式的IBD。因此，本研究旨在确定与婴儿期发病的IBD相关的基因变异。
我们从一名患有婴儿期发病IBD的男性患者及其非近亲结婚的韩国父母的全血样本中获取基因组DNA。使用三联体样本进行全外显子组测序。然后，我们使用IBD单基因形式和各种免疫缺陷的易感基因以及蛋白质结构分析来分析数据。
该患者在14天时出现口腔阿弗他溃疡，患有严重结肠炎且药物治疗无效。在该患者中发现了IL10RA基因的复合杂合突变（p.R101W；p.T179T）。此外，检测到位于X染色体上的补体因子备解素（CFP）基因的半合子突变（p.L456V），该突变从患者母亲遗传而来。蛋白质结构建模表明p.L456V可能损害备解素亚基相互作用，从而可能阻碍补体激活所需的蛋白质寡聚化。
本研究通过全外显子组测序在婴儿期发病的IBD中鉴定出IL10RA基因的复合杂合突变以及半合子CFP突变。CFP p.L456V可能通过干扰备解素的寡聚化而加重婴儿期发病IBD的症状。
