Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias.
Whole-exome sequencing identifies tetratricopeptide repeat domain 7A (TTC7A) mutations for combined immunodeficiency with intestinal atresias.
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DOI：
10.1016/j.jaci.2013.06.013
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发表时间：
2013-09
期刊：
影响因子：
--
通讯作者：
Notarangelo LD
中科院分区：
文献类型：
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作者：
Chen R;Giliani S;Lanzi G;Mias GI;Lonardi S;Dobbs K;Manis J;Im H;Gallagher JE;Phanstiel DH;Euskirchen G;Lacroute P;Bettinger K;Moratto D;Weinacht K;Montin D;Gallo E;Mangili G;Porta F;Notarangelo LD;Pedretti S;Al-Herz W;Alfahdli W;Comeau AM;Traister RS;Pai SY;Carella G;Facchetti F;Nadeau KC;Snyder M;Notarangelo LD
复合性免疫缺陷合并多发性肠闭锁（CID-MIA）是一种罕见的遗传性疾病，以肠梗阻和严重的免疫缺陷为特征。我们试图通过分析5名患者及其来自5个不相关家庭的健康直系亲属的外显子组序列来确定CID-MIA的潜在遗传原因。我们对5名CID-MIA患者和10名健康的CID-MIA直系亲属进行了全外显子组测序。我们还对另外3名CID-MIA患者进行了候选基因TTC7A的靶向Sanger测序。通过分析和比较这5个家族个体的外显子组序列，我们发现TTC7A基因存在双等位基因损伤突变，共有7个不同的突变。另外3例无关CID-MIA患者的靶向TTC7A基因测序显示，其中2例患者出现双等位基因有害突变，第三例患者出现异常剪接产物。正常胸腺染色显示TTC7A蛋白在胸腺上皮细胞和胸腺细胞中均有表达。此外，在两例CID-MIA患者的胸腺和外周淋巴组织中观察到严重的淋巴细胞缺失。我们在8例无关的CID-MIA患者中发现了TTC7A基因的有害突变，并证明TTC7A蛋白在胸腺中表达。我们的结果强烈提示TTC7A基因缺陷导致CID-MIA。在CID-MIA患者中应该仔细检查TTC7A基因的破坏性突变。表征该蛋白在免疫系统和肠道发育以及胸腺上皮细胞中的作用可能具有重要的治疗意义。
Combined Immunodeficiency with Multiple Intestinal Atresias (CID-MIA) is a rare hereditary disease characterized by intestinal obstructions and profound immune defects. We sought to determine the underlying genetic causes of CID-MIA by analyzing the exomic sequence of 5 patients and their healthy direct relatives from 5 unrelated families. We performed whole exome sequencing on 5 CID-MIA patients and 10 healthy direct family members belonging to 5 unrelated families with CID-MIA. We also performed targeted Sanger sequencing for the candidate gene TTC7A on 3 additional CID-MIA patients. Through analysis and comparison of the exomic sequence of the individuals from these 5 families, we identified biallelic damaging mutations in the TTC7A gene, for a total of 7 distinct mutations. Targeted TTC7A gene sequencing in 3 additional unrelated patients with CID-MIA revealed biallelic deleterious mutations in two of them, as well as an aberrant splice product in the third patient. Staining of normal thymus showed that the TTC7A protein is expressed in thymic epithelial cells as well as in thymocytes. Moreover, severe lymphoid depletion was observed in the thymus and peripheral lymphoid tissues from two patients with CID-MIA. We identified deleterious mutations of the TTC7A gene in 8 unrelated patients with CID-MIA and demonstrated that the TTC7A protein is expressed in the thymus. Our results strongly suggest that TTC7A gene defects cause CID-MIA. Damaging mutations in the gene TTC7A should be scrutinized in patients with CID-MIA. Characterization of the role of this protein in the immune system and intestinal development, as well as in thymic epithelial cells may have important therapeutic implications.
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