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Renal involvement and the role of Notch signalling in Alagille syndrome

Nature Reviews Nephrology volume 9, pages 409–418 (2013)Cite this article

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Abstract

Alagille syndrome is an autosomal dominant disorder with variable multisystem organ involvement that is caused by mutations in one of two genes in the Notch signalling pathway, JAG1 or NOTCH2. Alagille syndrome is characterized by bile duct paucity, along with at least three of the following features: cholestasis, cardiac defects, skeletal abnormalities, ocular abnormalities and characteristic facies. However, the clinical features of Alagille syndrome are highly variable, and children or adults may also present with predominantly renal findings and little or no hepatic involvement. Renal involvement occurs in 40% of JAG1-mutation-positive individuals. Renal insufficiency is common and has been specifically reported in children with Alagille syndrome who have end-stage liver disease. The role of NOTCH2 and JAG1 in formation of proximal nephron structures and podocytes might explain the observed phenotypes of renal dysplasia and proteinuria in patients with Alagille syndrome, and renal tubular acidosis may be the result of JAG1 expression in the collecting ducts. Renal vascular hypertension in patients with Alagille syndrome is explained by the widespread vasculopathy and the role of Notch signalling in vascular development. Increased awareness of Alagille syndrome amongst nephrologists may lead to more diagnoses of Alagille syndrome in patients with apparently isolated renal disease.

Key Points

  • Alagille syndrome is an autosomal dominant disorder with variable multisystem organ involvement

  • Classic features of Alagille syndrome include cholestatic liver disease, congenital cardiac disease (peripheral pulmonary stenosis), vasculopathy, renal pathology, skeletal features (butterfly vertebrae), ophthalmological involvement (posterior embryotoxon) and characteristic facies

  • Alagille syndrome can present at any age, even in adulthood, with predominantly renal and little or no hepatic involvement

  • Renal findings in Alagille syndrome include renal dysplasia (with or without cysts), renal tubular acidosis, vesicoureteral reflux, proteinuria and hypertension (with midaortic syndrome and/or visceral artery stenosis)

  • Renal pathology and vasculopathy have been recognized to be recurrent features of Alagille syndrome, which should be included in diagnostic criteria

  • Renal phenotypes in Alagille syndrome can be explained by the presence of mutations in the Notch signalling pathway genes, NOTCH2 or JAG1, during kidney development

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Figure 1: Clinical features of Alagille syndrome.
Figure 2: The Notch signalling pathway.
Figure 3: The temporal and spatial expression of NOTCH2 and JAG1 during kidney development.

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Acknowledgements

The authors' research work is supported by grants from the Canadian Institutes of Health Research, Kidney Foundation of Canada and the Canada Research Chairs Program (to N. D. Rosenblum) and by funding from the National Institute of Diabetes, Digestive and Kidney Diseases via the Childhood Liver Disease and Research Consortium: grant number U54DK078377 to B. M. Kamath and N. B. Spinner, and grant number DK081702 to N. B. Spinner.

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  1. The Hospital for Sick Children, 555 University Avenue, Toronto, M5G 1X8, Ontario, Canada

    Binita M. Kamath & Norman D. Rosenblum

  2. Department of Pathology, The Children's Hospital of Philadelphia, 1007A Abramson Research Centre, 3615 Civic Center Boulevard, Philadelphia, 19104, PA, USA

    Nancy B. Spinner

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B. M. Kamath researched the data for the article. B. M. Kamath, N. B. Spinner and N. D. Rosenblum contributed to writing, substantial contributions to discussions of the content, and review and/or editing of the manuscript before submission.

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Correspondence to Nancy B. Spinner.

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Kamath, B., Spinner, N. & Rosenblum, N. Renal involvement and the role of Notch signalling in Alagille syndrome. Nat Rev Nephrol 9, 409–418 (2013). https://doi.org/10.1038/nrneph.2013.102

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