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Mutations in DCDC2 (doublecortin domain-containing protein 2) in neonatal sclerosing cholangitis

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Tassos Grammatikopoulos, Melissa Sambrotta, Sandra Strautnieks, Pierre Foskett, A.S. Knisely, Bart Wagner, Maesha Deheragoda, Chris Starling, Giorgina Mieli-Vergani, Joshua Smith, University of Washington Center for Mendelian Genomics, Laura Bull, Richard J. Thompson

Original languageEnglish
Pages (from-to)1179–1187
JournalJournal of Hepatology
Issue number6
Early online date25 Jul 2016
Accepted/In press12 Jul 2016
E-pub ahead of print25 Jul 2016
Published1 Dec 2016


King's Authors


Background & aims 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. Methods 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. Results 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. Conclusion 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. Lay summary 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.

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