Before birth many functions required of the liver can be replaced by the placenta/mother. It is therefore in the first few months of life that the majoriy of congenital or genetic liver disease will present. The great majority of these diseases are cholestatic diseases, in which there is failure to make, or drain, bile from the liver into the intestine. A clinically defined group of patients was identified some years ago, and their disordertermed progressive familial intrahepatic cholestasis (PFIC). Significant advances in the understanding of the genetic basis of PFIC and related disorders have been made by the current applicants. However, we know that between one third and one half of these patients remain without a precise genetic diagnosis. This is partly due to limitations in the currently employed diagnostic pathways, which are also expensive and lengthy; however, it is due to a greater degree to our not having yet discovered all the causative genes. In this proposal, we bring together sample resources from the NIH-funded Childhood Liver Disease Research and Education Network (ChiLDREN), Dr. Bull's laboratory, and the 2 largest pediatric liver centers in Europe. By combining these sample resources and our experience in the field, with recent dramatic advances in genetic technology, we are poised to achieve the goals outlined here.
In Specific Aim 1 of the current study, we will seek to dramatically improve genetic diagnostic approaches, through the design and implementation of cost-effective, comprehensive screens for mutation in known cholestasis genes (i.e. genes mutated in forms of cholestasis). In so doing, we will define a cohort of patients without mutation in known genes, who are therefore suitable for inclusion in studies aimed at new gene discovery.
In Specific Aim 2, we will identify novel cholestasis genes using two powerful techniques. Firstly, DNA from children of closely related parents will be genotyped on SNP (single nucleotide polymorphism) arrays, and regions of homozygosity identified, to map genetic regions containing disease genes; promising candidate genes will then be sequenced in patients. Secondly, in selected patients, all known genes will be sequenced. This approach, termed 'whole-exome sequencing,' is remarkably efficient and cost-effective. The exome sequence will be analyzed to identify candidate disease mutations, and results confirmed in a larger patient set. The data gained from the gene discovery components of the study will be used to refine the diagnostic testing pathway in an iterative fashion. The result of our proposed studies will be the identification of new genes involved in these diseases, which will inevitably shed light on basic physiology, and lead to development of robust, rapid and affordable diagnostic testing. These goals are central to both the strategy of the Childhood Liver Disease Research and Education Network (ChiLDREN) and the mission of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), as stated in its Action Plan for Liver Disease Research.

Public Health Relevance

Fifteen children are diagnosed with liver disease each day in the US. Last year 560 children received a liver transplant in this country, and another 65 died whilst awaiting one. The great majority of these transplants were for cholestatic liver disease. This study is aimed at understanding the genetic causes of this group of conditions in children. Better understanding of the causes of cholestatic liver disease will improve diagnostic techniques, and is the first step toward improving treatment.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZDK1-GRB-J (J3))
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Karp, Robert W
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Bull, Laura N; Pawlikowska, Ludmila; Strautnieks, Sandra et al. (2018) Outcomes of surgical management of familial intrahepatic cholestasis 1 and bile salt export protein deficiencies. Hepatol Commun 2:515-528
Thompson, Richard J; Bull, Laura N (2015) Treating genetic disease: Expanding the options. Hepatology 62:349-51
Sambrotta, Melissa; Strautnieks, Sandra; Papouli, Efterpi et al. (2014) Mutations in TJP2 cause progressive cholestatic liver disease. Nat Genet 46:326-8