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Alagille Syndrome: Genetics and Functional Models

  • Pathobiology of Orphan Diseases (S Ranganathan, Section Editor)
  • Published:
Current Pathobiology Reports

Abstract

Purpose of Review

We review the genetics of the autosomal dominant, multi-system disorder Alagille syndrome, and provide a summary on how current functional models and emerging biotechnologies are equipped to guide scientists towards novel therapies. The importance of haploinsufficiency as a disease mechanism will be underscored throughout this discussion.

Recent Findings

Alagille syndrome, a human disorder affecting the liver, heart, vasculature, kidney, and other systems, is caused by mutations in the Notch signaling pathway ligand, Jagged1 (JAG1) or the receptor, NOTCH2. Current advances in animal modeling, in vitro cell culture, and human-induced pluripotent stem cells provide new opportunities in which to study disease mechanisms and manifestations.

Summary

We anticipate that the availability of innovative functional models will allow scientists to test new gene therapies or small molecule treatments in physiologically-relevant systems. With these advances, we look forward to the development of new methods to help Alagille syndrome patients.

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Acknowledgements

We would like to thank Ellen Tsai, Kathy Loomes, Marcella Devoto, Ian Krantz, David Piccoli, and Binita Kamath for continued collaboration. We are grateful to the many people who have contributed to our understanding of the genetics of Alagille syndrome including Ian Krantz, Ray Colliton, Jennifer Morrissette, Dan Warthen, Ryan McDaniell, Rob Bauer, Laura Leonard, Christopher Grochowski, and Ramakrishnan Rajagopalan. Parts of this work were supported by R01DK081702.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, 1012 Abramson Research Center, The Children’s Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA, USA

    Melissa A. Gilbert & Nancy B. Spinner

  2. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Nancy B. Spinner

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  1. Melissa A. Gilbert
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Correspondence to Nancy B. Spinner.

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Conflict of Interest

Nancy Spinner reports a patent issued for Human Jagged1 Polypeptide Encoding Nucleic Acids and Methods.

Melissa Gilbert declares no conflicts of interest.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

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This article is part of the Topical Collection on Pathobiology of Orphan Diseases

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Gilbert, M.A., Spinner, N.B. Alagille Syndrome: Genetics and Functional Models. Curr Pathobiol Rep 5, 233–241 (2017). https://doi.org/10.1007/s40139-017-0144-8

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