title: Mutations in DCDC2 (doublecortin domain containing protein 2) in neonatal sclerosing cholangitis.
abstract: 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 the doublecortin domain containing 2 gene (DCDC2), which encodes DCDC2 protein and is 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 patients carrying DCDC2 mutations, one died awaiting LT; five came to LT, of whom one died 2years 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.
authors.affiliation: Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK; Institute of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, King's College London, London, UK. Electronic address: t.grammatikopoulos@nhs.net.
authors.forename: Tassos
authors.initials: T
authors.lastname: Grammatikopoulos
authors.affiliation: Institute of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, King's College London, London, UK.
authors.forename: Melissa
authors.initials: M
authors.lastname: Sambrotta
authors.affiliation: Institute of Liver Studies, King's College Hospital, London, UK.
authors.forename: Sandra
authors.initials: S
authors.lastname: Strautnieks
authors.affiliation: Institute of Liver Studies, King's College Hospital, London, UK.
authors.forename: Pierre
authors.initials: P
authors.lastname: Foskett
authors.affiliation: Institute of Liver Studies, King's College Hospital, London, UK.
authors.forename: A S
authors.initials: AS
authors.lastname: Knisely
authors.affiliation: Histopathology Department, Royal Hallamshire Hospital, Sheffield, UK.
authors.forename: Bart
authors.initials: B
authors.lastname: Wagner
authors.affiliation: Institute of Liver Studies, King's College Hospital, London, UK.
authors.forename: Maesha
authors.initials: M
authors.lastname: Deheragoda
authors.affiliation: Institute of Liver Studies, King's College Hospital, London, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Starling
authors.affiliation: Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK; Institute of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, King's College London, London, UK.
authors.forename: Giorgina
authors.initials: G
authors.lastname: Mieli-Vergani
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Smith
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA, USA.
authors.affiliation: Liver Center Laboratory, Department of Medicine and Institute for Human Genetics, University of California San Francisco, CA, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Bull
authors.affiliation: Paediatric Liver, GI & Nutrition Centre, King's College Hospital, London, UK; Institute of Liver Studies, Division of Transplantation Immunology and Mucosal Biology, King's College London, London, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Thompson
mesh_terms: D015209:Cholangitis, Sclerosing / Q000235:genetics*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation
chemical_list: C510451:DCDC2 protein, human; D008869:Microtubule-Associated Proteins
keywords: Acetylated alpha-tubulin; Cholangiopathy; Ciliopathy; Doublecortin domain containing protein 2; Neonate