DCDC2 Mutations Cause Neonatal Sclerosing Cholangitis.
Neonatal sclerosing cholangitis (NSC) is a rare biliary disease leading to liver transplantation in childhood. Patients with NSC and ichtyosis have already been identified with a CLDN1 mutation, encoding a tight-junction protein. However, for the majority of patients, the molecular basis of NSC remains unknown. We identified biallelic missense mutations or in-frame deletion in DCDC2 in four affected children. Mutations involve highly conserved amino acids in the doublecortin domains of the protein. In cholangiocytes, DCDC2 protein is normally located in the cytoplasm and cilia, whereas in patients the mutated protein is accumulated in the cytoplasm, absent from cilia, and associated with ciliogenesis defect. This is the first report of DCDC2 mutations in NSC. This data expands the molecular spectrum of NSC, that can be considered as a ciliopathy and also expands the clinical spectrum of the DCDC2 mutations, previously reported in dyslexia, deafness, and nephronophtisis.
Hepatology Unit, Necker Hospital, Assistance Publique-Hopitaux de Paris, France. muriel.girard@aphp.fr.|Paris Descartes Sorbonne Paris Cité University, Imagine institute, Paris, France. muriel.girard@aphp.fr.|Inserm UMR-1163, Laboratory of Embryology and Genetics of Human Malformations, Paris, France. muriel.girard@aphp.fr.
Muriel
M
Girard
Paris Descartes Sorbonne Paris Cité University, Imagine institute, Paris, France.|Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases, Paris, France.
Albane A
AA
Bizet
Service d'Hépatologie, Gastroentérologie et Nutrition Pédiatriques, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, Bron, France.|Université Claude Bernard Lyon 1, Lyon, France.
Alain
A
Lachaux
Pediatric Hepatology and Liver Transplantation Unit, Reference Centre for Pediatric Liver Diseases, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, France.|Université Paris-Sud 11, France.
Emmanuel
E
Gonzales
Paris Descartes Sorbonne Paris Cité University, Imagine institute, Paris, France.|Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases, Paris, France.
Emilie
E
Filhol
Université Claude Bernard Lyon 1, Lyon, France.|Service de Pathologie, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.
Sophie
S
Collardeau-Frachon
Paris Descartes Sorbonne Paris Cité University, Imagine institute, Paris, France.|Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases, Paris, France.
Cécile
C
Jeanpierre
Paris Descartes Sorbonne Paris Cité University, Imagine institute, Paris, France.|Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases, Paris, France.
Charline
C
Henry
Pathology Department, Necker Hospital, Assistance Publique-Hôpitaux de Paris, France.
Monique
M
Fabre
Université Claude Bernard Lyon 1, Lyon, France.|Hospices Civils de Lyon, Département D'imagerie Digestive, Hôpital E. Herriot, Lyon, France.
Loic
L
Viremouneix
Pathology Department, Necker Hospital, Assistance Publique-Hôpitaux de Paris, France.
Louise
L
Galmiche
Hepatology Unit, Necker Hospital, Assistance Publique-Hopitaux de Paris, France.
Dominique
D
Debray
Inserm UMR-1163, Genomic Core Facility, Paris, France.
Christine
C
Bole-Feysot
Inserm UMR-1163, Bioinformatic Core Facility, Paris, France.
Patrick
P
Nitschke
Université Paris-Sud 11, France.|Department of Pediatric Radiology, Bicêtre Hospital, Le Kremlin-Bicêtre, France.
Danièle
D
Pariente
Université Paris-Sud 11, France.|Service d'Anatomopathologie, AP-HP Hôpital Kremlin-Bicêtre, Paris, France.
Catherine
C
Guettier
Paris Descartes Sorbonne Paris Cité University, Imagine institute, Paris, France.|Inserm UMR-1163, Laboratory of Embryology and Genetics of Human Malformations, Paris, France.
Stanislas
S
Lyonnet
Paris Descartes Sorbonne Paris Cité University, Imagine institute, Paris, France.|Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases, Paris, France.
Laurence
L
Heidet
Université Claude Bernard Lyon 1, Lyon, France.|Néphrogones, Centre de Référence des Maladies Rénales Rares, Hospices Civils de Lyon, Bron, France.
Aurelia
A
Bertholet
Pediatric Hepatology and Liver Transplantation Unit, Reference Centre for Pediatric Liver Diseases, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, France.|Université Paris-Sud 11, France.
Emmanuel
E
Jacquemin
Paris Descartes Sorbonne Paris Cité University, Imagine institute, Paris, France.
Alexandra
A
Henrion-Caude
Paris Descartes Sorbonne Paris Cité University, Imagine institute, Paris, France.|Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases, Paris, France.
Sophie
S
Saunier
D015209:Cholangitis, Sclerosing / Q000235:genetics* / Q000378:metabolism; D002923:Cilia / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D000072417:Protein Domains; D017384:Sequence Deletion
C510451:DCDC2 protein, human; D008869:Microtubule-Associated Proteins
DCDC2; biliary cirrhosis; ciliopathy, doublecortin domain; hyperechogenic kidney; neonatal sclerosing cholangitis