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

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Mutations in DCDC2 (doublecortin domain-containing protein 2) in neonatal sclerosing cholangitis. / Grammatikopoulos, Tassos; Sambrotta, Melissa; Strautnieks, Sandra; Foskett, Pierre; Knisely, A.S.; Wagner, Bart; Deheragoda, Maesha; Starling, Chris; Mieli-Vergani, Giorgina; Smith, Joshua; Genomics, University of Washington Center for Mendelian; Bull, Laura; Thompson, Richard J.

In: Journal of Hepatology, Vol. 65, No. 6, 25.07.2016, p. 1179–1187.

Research output: Contribution to journalArticle

Harvard

Grammatikopoulos, T, Sambrotta, M, Strautnieks, S, Foskett, P, Knisely, AS, Wagner, B, Deheragoda, M, Starling, C, Mieli-Vergani, G, Smith, J, Genomics, UOWCFM, Bull, L & Thompson, RJ 2016, 'Mutations in DCDC2 (doublecortin domain-containing protein 2) in neonatal sclerosing cholangitis', Journal of Hepatology, vol. 65, no. 6, pp. 1179–1187. https://doi.org/10.1016/j.jhep.2016.07.017

APA

Grammatikopoulos, T., Sambrotta, M., Strautnieks, S., Foskett, P., Knisely, A. S., Wagner, B., ... Thompson, R. J. (2016). Mutations in DCDC2 (doublecortin domain-containing protein 2) in neonatal sclerosing cholangitis. Journal of Hepatology, 65(6), 1179–1187. https://doi.org/10.1016/j.jhep.2016.07.017

Vancouver

Grammatikopoulos T, Sambrotta M, Strautnieks S, Foskett P, Knisely AS, Wagner B et al. Mutations in DCDC2 (doublecortin domain-containing protein 2) in neonatal sclerosing cholangitis. Journal of Hepatology. 2016 Jul 25;65(6):1179–1187. https://doi.org/10.1016/j.jhep.2016.07.017

Author

Grammatikopoulos, Tassos ; Sambrotta, Melissa ; Strautnieks, Sandra ; Foskett, Pierre ; Knisely, A.S. ; Wagner, Bart ; Deheragoda, Maesha ; Starling, Chris ; Mieli-Vergani, Giorgina ; Smith, Joshua ; Genomics, University of Washington Center for Mendelian ; Bull, Laura ; Thompson, Richard J. / Mutations in DCDC2 (doublecortin domain-containing protein 2) in neonatal sclerosing cholangitis. In: Journal of Hepatology. 2016 ; Vol. 65, No. 6. pp. 1179–1187.

Bibtex Download

@article{8e35da7a6fdd410f9c46cc313b8e836f,
title = "Mutations in DCDC2 (doublecortin domain-containing protein 2) in neonatal sclerosing cholangitis",
abstract = "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.",
keywords = "Neonate, Cholangiopathy, Doublecortin domain-containing protein 2, Ciliopathy, Acetylated alpha tubulin",
author = "Tassos Grammatikopoulos and Melissa Sambrotta and Sandra Strautnieks and Pierre Foskett and A.S. Knisely and Bart Wagner and Maesha Deheragoda and Chris Starling and Giorgina Mieli-Vergani and Joshua Smith and Genomics, {University of Washington Center for Mendelian} and Laura Bull and Thompson, {Richard J.}",
year = "2016",
month = "7",
day = "25",
doi = "10.1016/j.jhep.2016.07.017",
language = "English",
volume = "65",
pages = "1179–1187",
journal = "Journal of Hepatology",
issn = "0168-8278",
publisher = "ELSEVIER SCIENCE BV",
number = "6",

}

RIS (suitable for import to EndNote) Download

TY - JOUR

T1 - Mutations in DCDC2 (doublecortin domain-containing protein 2) in neonatal sclerosing cholangitis

AU - Grammatikopoulos, Tassos

AU - Sambrotta, Melissa

AU - Strautnieks, Sandra

AU - Foskett, Pierre

AU - Knisely, A.S.

AU - Wagner, Bart

AU - Deheragoda, Maesha

AU - Starling, Chris

AU - Mieli-Vergani, Giorgina

AU - Smith, Joshua

AU - Genomics, University of Washington Center for Mendelian

AU - Bull, Laura

AU - Thompson, Richard J.

PY - 2016/7/25

Y1 - 2016/7/25

N2 - 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.

AB - 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.

KW - Neonate

KW - Cholangiopathy

KW - Doublecortin domain-containing protein 2

KW - Ciliopathy

KW - Acetylated alpha tubulin

U2 - 10.1016/j.jhep.2016.07.017

DO - 10.1016/j.jhep.2016.07.017

M3 - Article

VL - 65

SP - 1179

EP - 1187

JO - Journal of Hepatology

JF - Journal of Hepatology

SN - 0168-8278

IS - 6

ER -

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