DCDC2 Mutations Cause Neonatal Sclerosing Cholangitis |
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| Authors: | Muriel Girard Albane A. Bizet Alain Lachaux Emmanuel Gonzales Emilie Filhol Sophie Collardeau‐Frachon Cécile Jeanpierre Charline Henry Monique Fabre Loic Viremouneix Louise Galmiche Dominique Debray Christine Bole‐Feysot Patrick Nitschke Danièle Pariente Catherine Guettier Stanislas Lyonnet Laurence Heidet Aurelia Bertholet Emmanuel Jacquemin Alexandra Henrion‐Caude Sophie Saunier |
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| Affiliation: | 1. Hepatology Unit, Necker Hospital, Assistance Publique‐Hopitaux de Paris, France;2. Paris Descartes Sorbonne Paris Cité University, Imagine institute, Paris, France;3. Inserm UMR‐1163, Laboratory of Embryology and Genetics of Human Malformations, Paris, France;4. Inserm UMR‐1163, Laboratory of Hereditary Kidney Diseases, Paris, France;5. Service d'Hépatologie, Gastroentérologie et Nutrition Pédiatriques, H?pital Femme‐Mère‐Enfant, Bron, France;6. Université Claude Bernard Lyon 1, Lyon, France;7. Pediatric Hepatology and Liver Transplantation Unit, Reference Centre for Pediatric Liver Diseases, Bicêtre Hospital, Assistance Publique‐H?pitaux de Paris, France;8. Université Paris‐Sud 11, France;9. Service de Pathologie, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France;10. Pathology Department, Necker Hospital, Assistance Publique‐H?pitaux de Paris, France;11. Hospices Civils de Lyon, Département D'imagerie Digestive, H?pital E. Herriot, Lyon, France;12. Inserm UMR‐1163, Genomic Core Facility, Paris, France;13. Inserm UMR‐1163, Bioinformatic Core Facility, Paris, France;14. Department of Pediatric Radiology, Bicêtre Hospital, France;15. Service d'Anatomopathologie, AP‐HP H?pital Kremlin‐Bicêtre, Paris, France;16. Néphrogones, Centre de Référence des Maladies Rénales Rares, Hospices Civils de Lyon, Bron, France |
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| Abstract: | 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. |
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| Keywords: | neonatal sclerosing cholangitis biliary cirrhosis DCDC2 ciliopathy, doublecortin domain hyperechogenic kidney |
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