DCDC2 Mutations Cause Neonatal Sclerosing Cholangitis

  • Hum Mutat. 2016 Oct;37(10):1025-9. doi: 10.1002/humu.23031.
Muriel Girard  1  2  3 ,  Albane A Bizet  4  5 ,  Alain Lachaux  6  7 ,  Emmanuel Gonzales  8  9 ,  Emilie Filhol  4  5 ,  Sophie Collardeau-Frachon  7  10 ,  Cécile Jeanpierre  4  5 ,  Charline Henry  4  5 ,  Monique Fabre  11 ,  Loic Viremouneix  7  12 ,  Louise Galmiche  11 ,  Dominique Debray  13 ,  Christine Bole-Feysot  14 ,  Patrick Nitschke  15 ,  Danièle Pariente  9  16 ,  Catherine Guettier  9  17 ,  Stanislas Lyonnet  4  18 ,  Laurence Heidet  4  5 ,  Aurelia Bertholet  7  19 ,  Emmanuel Jacquemin  8  9 ,  Alexandra Henrion-Caude  4 ,  Sophie Saunier  4  5
Affiliations
  • 1. Hepatology Unit, Necker Hospital, Assistance Publique-Hopitaux de Paris, France. [email protected].
  • 2. Paris Descartes Sorbonne Paris Cité University, Imagine institute, Paris, France. [email protected].
  • 3. Inserm UMR-1163, Laboratory of Embryology and Genetics of Human Malformations, Paris, France. [email protected].
  • 4. Paris Descartes Sorbonne Paris Cité University, Imagine institute, Paris, France.
  • 5. Inserm UMR-1163, Laboratory of Hereditary Kidney Diseases, Paris, France.
  • 6. Service d'Hépatologie, Gastroentérologie et Nutrition Pédiatriques, Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, Bron, France.
  • 7. Université Claude Bernard Lyon 1, Lyon, France.
  • 8. Pediatric Hepatology and Liver Transplantation Unit, Reference Centre for Pediatric Liver Diseases, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, France.
  • 9. Université Paris-Sud 11, France.
  • 10. Service de Pathologie, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.
  • 11. Pathology Department, Necker Hospital, Assistance Publique-Hôpitaux de Paris, France.
  • 12. Hospices Civils de Lyon, Département D'imagerie Digestive, Hôpital E. Herriot, Lyon, France.
  • 13. Hepatology Unit, Necker Hospital, Assistance Publique-Hopitaux de Paris, France.
  • 14. Inserm UMR-1163, Genomic Core Facility, Paris, France.
  • 15. Inserm UMR-1163, Bioinformatic Core Facility, Paris, France.
  • 16. Department of Pediatric Radiology, Bicêtre Hospital, Le Kremlin-Bicêtre, France.
  • 17. Service d'Anatomopathologie, AP-HP Hôpital Kremlin-Bicêtre, Paris, France.
  • 18. Inserm UMR-1163, Laboratory of Embryology and Genetics of Human Malformations, Paris, France.
  • 19. Néphrogones, Centre de Référence des Maladies Rénales Rares, Hospices Civils de Lyon, Bron, France.
PMID: 27319779 DOI: 10.1002/humu.23031
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.

Keywords
DCDC2; biliary cirrhosis; ciliopathy, doublecortin domain; hyperechogenic kidney; neonatal sclerosing cholangitis.