Doublecortin domain containing protein 2 (DCDC2) genetic variants in primary sclerosing cholangitis.
Doublecortin domain containing protein 2 (DCDC2) genetic variants in primary sclerosing cholangitis.
复制标题
原发性硬化性胆管炎中含有双皮质蛋白结构域的蛋白 2 (DCDC2) 遗传变异。
DOI：
10.1016/j.jhep.2017.02.036
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发表时间：
2017
影响因子：
25.7
通讯作者：
Lazaridis,KonstantinosN
中科院分区：
文献类型：
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作者：
Cheung,AngelaC;Juran,BrianD;Moore,RaymondM;LaRusso,NicholasF;Lazaridis,KonstantinosN
我们怀着极大的兴趣阅读了T. Grammatikopoulos等人报告了新生儿硬化性胆管炎（NSC）与含双皮质素结构域蛋白2（DCDC 2）功能缺失突变之间的相关性。1在电子显微镜下，这些患者的胆管细胞缺乏初级纤毛。虽然原发性硬化性胆管炎（PSC）与NSC是不同的实体，但PSC中观察到的病理相似性，包括纤毛异常，2表明两种疾病之间可能有一些潜在的致病机制。因此，我们有兴趣确定DCDC 2的潜在破坏性遗传变异（[ENST 00000378454]）是否也可能在PSC中发挥作用。为此，我们检查了67例PSC患者的可用全外显子组测序数据，其中30例在儿童期（< 18岁）诊断，37例为成人（> 18岁）。在这些组中，PSC诊断的中位年龄分别为14岁（范围5-17）和46岁（范围26-69）。DCDC 2在我们的测序数据中覆盖良好，整个基因的平均读取深度为80- 100倍。在质量控制步骤和去除极其常见的变体（次要等位基因频率> 0.2）和位于蛋白质编码序列之外的那些变体之后，我们鉴定了三种错义变体（c. 1368A> T_p.Lys456Asn，c. 661A> G_p.Ser221Gly，c. 454 C> G_p.Pro152Ala）。重要的是，预测这些变体都不会对蛋白质产生严重影响，并且没有证据表明错义变体具有复合杂合性。
We read with great interest the study by T. Grammatikopoulos et al. that reported an association between neonatal sclerosing cholangitis (NSC) and loss of function mutations in doublecortin domain containing protein 2 (DCDC2). 1 On electron microscopy, the cholangiocytes of these patients lacked primary cilia.While primary sclerosing cholangitis (PSC) is a different entity than NSC, pathologic similarities, including cilia abnormalities observed in PSC, 2 suggest that some of the underlying pathogenic mechanisms could be shared between the two diseases. Thus, we were interested to determine whether potentially damaging genetic variants of DCDC2 ([ENST00000378454]) might also play a role in PSC. To this end, we examined available whole exome sequencing data for 67 PSC patients, 30 of whom were diagnosed in childhood (< 18 years of age) and 37 as adults (> 18 years of age). The median age of PSC diagnosis was 14 years (range 5–17) and 46 years (range 26–69) in these groups, respectively. DCDC2 was covered well in our sequencing data, with read-depth averaging 80–100x across the gene. Following quality control steps and removing extremely common variants (minor allele frequency> 0.2) and those located outside of the protein-coding sequence, we identified three missense variants (c. 1368A> T_p. Lys456Asn, c. 661A> G_p. Ser221Gly, c. 454C> G_p. Pro152Ala) among the 67 patients. Importantly, none of these variants were predicted to have a severe impact on the protein and there was no evidence of compound heterozygosity of the missense variants.