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NOTCH2 mutations in Alagille syndrome
  1. Binita Maya Kamath1,
  2. Robert C Bauer2,
  3. Kathleen M Loomes3,
  4. Grace Chao2,
  5. Jennifer Gerfen2,
  6. Anne Hutchinson2,
  7. Winita Hardikar4,
  8. Gideon Hirschfield5,
  9. Paloma Jara6,
  10. Ian D Krantz7,
  11. Pablo Lapunzina8,
  12. Laura Leonard2,
  13. Simon Ling1,
  14. Vicky Lee Ng1,
  15. Phuc Le Hoang9,
  16. David A Piccoli3,
  17. Nancy Bettina Spinner2
  1. 1Division of Gastroenterology and Nutrition, Department of Pediatrics, The Hospital for Sick Children and University of Toronto, Canada
  2. 2Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia and The Perelman School of Medicine, The University of Pennsylvania, Philadelphia Pennsylvania, USA
  3. 3Division of Gastroenterology and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia and The Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
  4. 4Division of Liver and Intestinal Transplantation, Department of Gastroenterology, Royal Children's Hospital Melbourne, Australia
  5. 5Department of Medicine, University of Toronto, Ontario, Canada
  6. 6Division of Pediatric Hepatology, Hospital Universitario La Paz, IdiPaz, Madrid, Spain
  7. 7Division of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia and The Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pennsylvania, USA
  8. 8Instituto de Genética Médica y Molecular (INGEMM), IDIPAZ-Hospital Universitario La Paz, Universidad Autónoma de Madrid, Spain
  9. 9Department of Gastroenterology, Children's Hospital # 1, Ho Chi Minh City, Vietnam
  1. Correspondence to Professor Nancy B Spinner, Children's Hospital of Philadelphia, Department of Pathology and Laboratory Medicine, 1007A Abramson Research Center, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA; spinner{at}mail.med.upenn.edu

Abstract

Background Alagille syndrome (ALGS) is a dominant, multisystem disorder caused by mutations in the Jagged1 (JAG1) ligand in 94% of patients, and in the NOTCH2 receptor in <1%. There are only two NOTCH2 families reported to date. This study hypothesised that additional NOTCH2 mutations would be present in patients with clinical features of ALGS without a JAG1 mutation.

Methods The study screened a cohort of JAG1-negative individuals with clinical features suggestive or diagnostic of ALGS for NOTCH2 mutations.

Results Eight individuals with novel NOTCH2 mutations (six missense, one splicing, and one non-sense mutation) were identified. Three of these patients met classic criteria for ALGS and five patients only had a subset of features. The mutations were distributed across the extracellular (N=5) and intracellular domains (N=3) of the protein. Functional analysis of four missense, one nonsense, and one splicing mutation demonstrated decreased Notch signalling of these proteins. Subjects with NOTCH2 mutations demonstrated highly variable expressivity of the affected systems, as with JAG1 individuals. Liver involvement was universal in NOTCH2 probands and they had a similar prevalence of ophthalmologic and renal anomalies to JAG1 patients. There was a trend towards less cardiac involvement in the NOTCH2 group (60% vs 100% in JAG1). NOTCH2 (+) probands exhibited a significantly decreased penetrance of vertebral abnormalities (10%) and facial features (20%) when compared to the JAG1 (+) cohort.

Conclusions This work confirms the importance of NOTCH2 as a second disease gene in ALGS and expands the repertoire of the NOTCH2 related disease phenotype.

  • Alagille syndrome
  • notch signalling pathway
  • JAGGED1
  • NOTCH2

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Footnotes

  • Funding This study was supported by funding from the NIDDK (1R01DK081702 to NBS) and the Fred and Susanne Biesecker Liver center (NBS, DAP, KML).

  • Competing interests None.

  • Ethics approval Institutional Review Board at the Children's Hospital of Philadelphia and the Review Ethics Board at the Hospital for Sick Children, Toronto.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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