This is a proposal to identify clinically relevant modifiers of the severity of hepatic disease in patients with Alagille Syndrome (AGS) AGS is an autosomal dominant, multi-system, variably expressed disorder caused by mutations in one of two Notch Signaling Pathway genes. Mutations in Jagged1 (JAG1) are found in 95% of patients and mutations in Notch2 in less than 1%. AGS causes significant morbidity associated with liver, cardiac, renal and vascular malformations. The liver disease in AGS is characterized pathologically by intrahepatic bile duct paucity, with resulting cholestasis, and ranges from very mild (sub-clinical with only biochemical abnormalities of liver enzymes) to severe, in which case liver damage is extensive and a transplant is required. Mortality due to liver disease is about 5%. The highly variable expressivity is consistent with the presence of modifying factors that contribute to expressivity. We hypothesize that there are genetic modifiers of the severity of liver disease. We propose a multi-pronged approach to the identification of these genetic modifiers. Using our well-characterized cohort of patients with AGS and JAG1 mutations, we will compare patients with mild liver disease to patients with severe liver disease to look for evidence of genomic differences between the two groups. Recognizing the importance of attaining adequate power for the proposed studies, we will aggressively recruit additional patients. We will use multiple techniques to look for genetic differences between the patients with mild liver disease versus those with severe liver disease. We will test for association of copy number variants with liver disease severity. We will carry out a genome-wide association study using random tagSNPs and SNPs in specific genomic regions (candidate genes). We anticipate that identification of modifying factors for liver disease severity will have implications beyond Alagille syndrome patients, and may point to modifiers of liver disease severity in other disorders associated with cholestasis.

Public Health Relevance

This project aims to identify modifiers of liver disease severity in Alagille syndrome. Severe liver disease in AGS is an important cause of liver transplantation, and 20% of AGS die as a result of liver disease. Identification of genetic factors associated with severe liver disease will have important implications for prognosis, and it is our hope that this will lead to improved therapies, as the pathways underlying liver disease progression are revealed. This may have implications for other cholestatic liver diseases as well.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK081702-03
Application #
8097573
Study Section
Special Emphasis Panel (ZDK1-GRB-W (J2))
Program Officer
Karp, Robert W
Project Start
2009-07-01
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
3
Fiscal Year
2011
Total Cost
$821,952
Indirect Cost
Name
Children's Hospital of Philadelphia
Department
Type
DUNS #
073757627
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Gilbert, Melissa A; Spinner, Nancy B (2017) Alagille syndrome: Genetics and Functional Models. Curr Pathobiol Rep 5:233-241
Izumi, Kosuke; Hayashi, Daisuke; Grochowski, Christopher M et al. (2016) Discordant clinical phenotype in monozygotic twins with Alagille syndrome: Possible influence of non-genetic factors. Am J Med Genet A 170A:471-5
Mouzaki, Marialena; Bass, Lee M; Sokol, Ronald J et al. (2016) Early life predictive markers of liver disease outcome in an International, Multicentre Cohort of children with Alagille syndrome. Liver Int 36:755-60
Grochowski, Christopher M; Loomes, Kathleen M; Spinner, Nancy B (2016) Jagged1 (JAG1): Structure, expression, and disease associations. Gene 576:381-4
Tsai, Ellen A; Gilbert, Melissa A; Grochowski, Christopher M et al. (2016) THBS2 Is a Candidate Modifier of Liver Disease Severity in Alagille Syndrome. Cell Mol Gastroenterol Hepatol 2:663-675.e2
Rajagopalan, Ramakrishnan; Grochowski, Christopher M; Gilbert, Melissa A et al. (2016) Compound heterozygous mutations in NEK8 in siblings with end-stage renal disease with hepatic and cardiac anomalies. Am J Med Genet A 170:750-3
Grochowski, Christopher M; Rajagopalan, Ramakrishnan; Falsey, Alexandra M et al. (2015) Exome sequencing reveals compound heterozygous mutations in ATP8B1 in a JAG1/NOTCH2 mutation-negative patient with clinically diagnosed Alagille syndrome. Am J Med Genet A 167A:891-3
Leonard, Laura D; Chao, Grace; Baker, Alastair et al. (2014) Clinical utility gene card for: Alagille Syndrome (ALGS). Eur J Hum Genet 22:
Kamath, Binita M; Spinner, Nancy B; Rosenblum, Norman D (2013) Renal involvement and the role of Notch signalling in Alagille syndrome. Nat Rev Nephrol 9:409-18
Lin, Henry C; Le Hoang, Phuc; Hutchinson, Anne et al. (2012) Alagille syndrome in a Vietnamese cohort: mutation analysis and assessment of facial features. Am J Med Genet A 158A:1005-13

Showing the most recent 10 out of 19 publications