Mutations in DCDC2 (doublecortin domain containing protein 2) in neonatal sclerosing cholangitis.
Mutations in DCDC2 (doublecortin domain containing protein 2) in neonatal sclerosing cholangitis.
复制标题
DOI：
10.1016/j.jhep.2016.07.017
复制
发表时间：
2016-12
影响因子：
25.7
通讯作者：
Thompson RJ
中科院分区：
文献类型：
--
作者：
Grammatikopoulos T;Sambrotta M;Strautnieks S;Foskett P;Knisely AS;Wagner B;Deheragoda M;Starling C;Mieli-Vergani G;Smith J;University of Washington Center for Mendelian Genomics;Bull L;Thompson RJ
新生儿硬化性胆管炎（NSC）是一种严重的泌尿系发病的胆管疾病，通常导致肝移植（LT）治疗儿童期终末期肝病。肝活检结果在组织病理学上类似于胆道闭锁（BA）;然而，在NSC肝外胆管是开放的，而在BA他们的管腔闭塞。NSC常见于近亲染色体，提示常染色体隐性遗传。从确定的29例NSC患者（24个家庭）中，24例（21个家庭）中可获得DNA。选择13例（7例男性）血缘关系的患者（12个家庭）进行全外显子测序。对序列变体进行纯合性、致病性、次要等位基因频率、质量评分和编码蛋白表达模式的筛选。13例患者中有4例是纯合子，2例是复合杂合子，突变的DCDC 2，编码双皮质素结构域2（DCDC 2），表达在胆管细胞纤毛。另外11例患者进行了测序：1例（有一对同胞）是DCDC 2突变的复合杂合子。所有突变均为蛋白质截短。在DCDC 2突变患者的可用肝组织中，人DCDC 2和纤毛蛋白乙酰化α-微管蛋白（ACALT）的免疫染色显示无表达（n=6），透射电子显微镜发现胆管细胞缺乏初级纤毛（n=5）。DCDC 2和ACALT在无DCDC 2突变的NSC患者中表达（n=22）。在DCDC 2中，1例患者在等待LT时死亡; 5例患者接受LT，其中1例在2年后死亡。其他四个都很好。在24例有DNA的NSC患者中，7例DCDC 2突变（19个家族中的6个）。相当比例的NSC患者在DCDC 2中具有突变。他们的疾病代表了一种新的肝脏为基础的纤毛病变。新生儿硬化性胆管炎（NSC）是一种罕见的遗传形式的肝脏疾病，出现在婴儿期。通过下一代测序技术，我们在一组NSC儿童中鉴定了编码含双皮质素结构域2（DCDC 2）蛋白的基因突变。DCDC 2是在胆管细胞的初级纤毛中发现的信号传导和结构蛋白。胆管细胞是形成胆道系统的细胞，胆道系统是肝脏的引流系统。
Neonatal sclerosing cholangitis (NSC) is a severe neonatal-onset cholangiopathy commonly leading to liver transplantation (LT) for end-stage liver disease in childhood. Liver-biopsy findings histopathologically resemble those in biliary atresia (BA); however, in NSC extrahepatic bile ducts are patent, whilst in BA their lumina are obliterated. NSC is commonly seen in consanguineous kindreds, suggesting autosomal recessive inheritance. From 29 NSC patients (24 families) identified, DNA was available in 24 (21 families). Thirteen (7 male) patients (12 families) of consanguineous parentage were selected for whole exome sequencing. Sequence variants were filtered for homozygosity, pathogenicity, minor allele frequency, quality score, and encoded-protein expression pattern. Four of 13 patients were homozygous and two were compound heterozygous for mutations in DCDC2, encoding doublecortin domain containing 2 (DCDC2), expressed in cholangiocyte cilia. Another 11 patients were sequenced: one (with one sibling pair) was compound heterozygous for DCDC2 mutations. All mutations were protein-truncating. In available liver tissue from patients with DCDC2 mutations, immunostaining for human DCDC2 and the ciliary protein acetylated alpha-tubulin (ACALT) showed no expression (n=6) and transmission electron microscopy found that cholangiocytes lacked primary cilia (n=5). DCDC2 and ACALT were expressed in NSC patients without DCDC2 mutations (n=22). Of the DCDC2, one patient died awaiting LT; five came to LT, of whom one died 2 years later. The other 4 are well. Among 24 NSC patients with available DNA, 7 had mutations in DCDC2 (6 of 19 families). NSC patients in substantial proportion harbour mutations in DCDC2. Their disease represents a novel liver-based ciliopathy. Neonatal sclerosing cholangitis (NSC) is a rare genetic form of liver disease presenting in infancy. Through Next Generation Sequencing we identified mutations in the gene encoding for doublecortin domain containing 2 (DCDC2) protein in a group of NSC children. DCDC2 is a signalling and structural protein found in primary cilia of cholangiocytes. Cholangiocytes are the cells forming the biliary system which is the draining system of the liver.
登录
查看更多内容
影响因子：
10.5
作者：
Harris PC;Torres VE
通讯作者：
Torres VE
影响因子：
3.2
作者：
Mieli-Vergani, G;Vergani, D
通讯作者：
Vergani, D
DOI：
10.1038/modpathol.2011.212
发表时间：
2012-05
期刊：
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.1
作者：
AMEDEEMANESME, O;BERNARD, O;ALAGILLE, D
通讯作者：
ALAGILLE, D
影响因子：
2.4
作者：
Davenport, M;Kerkar, N;Howard, ER
通讯作者：
Howard, ER