The goals of this project are to identify and characterize the molecular bases for two forms of inherited liver disease, cholestasis-lymphedema syndrome (CLS) and familial hyperbileacidemia (FHB). We will work toward this goal through the following three specific aims: 1) identify the gene mutated in CLS, and further genetically characterize this disorder; 2) characterize the expression pattern of the CLS gene and protein; and 3) identify the gene mutated in FHB, and further genetically characterize this disorder. These genes will be genetically localized through use of recently developed, highly efficient genetic mapping techniques, and then candidate genes identified through analysis of available sequence databases, and use of laboratory-based gene identification techniques. Mutations causing CLS and FHB will be identified, and clinical data examined to identify any correlations between the type of mutation present in a patient, and the characteristics of that patient's disease. The types of cells in which the CLS gene is expressed will be identified using in situ hybridization approaches, and the cellular and subcellular localization of the CLS protein will be characterized, using immunohistochemical techniques. The identification of genes mutated in hereditary disorders, and the subsequent characterization of their protein products, has become a valuable tool for increasing our understanding of the pathophysiology of diseases, including disorders of the hepatobiliary system, which affect millions of people in the U.S. Identification of the genetic cause of a disease assists in diagnosis, and also aids further study that may lead to better treatment and prevention. Most importantly, the identification of a disease gene provides specific insight into the biological pathways that are deranged in the illness, and tools for further study of these pathways.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK058214-01A1
Application #
6325448
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Doo, Edward
Project Start
2001-09-30
Project End
2005-07-31
Budget Start
2001-09-30
Budget End
2002-07-31
Support Year
1
Fiscal Year
2001
Total Cost
$232,313
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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
Bull, Laura N; Hu, Donglei; Shah, Sohela et al. (2015) Intrahepatic Cholestasis of Pregnancy (ICP) in U.S. Latinas and Chileans: Clinical features, Ancestry Analysis, and Admixture Mapping. PLoS One 10:e0131211
Bull, Laura N; Vargas, Juan (2014) Serum bile acids in intrahepatic cholestasis of pregnancy: not just a diagnostic test. Hepatology 59:1220-2
Setchell, Kenneth D R; Heubi, James E; Shah, Sohela et al. (2013) Genetic defects in bile acid conjugation cause fat-soluble vitamin deficiency. Gastroenterology 144:945-955.e6; quiz e14-5
Shah, Sohela; Conlin, Laura K; Gomez, Luis et al. (2013) CCBE1 mutation in two siblings, one manifesting lymphedema-cholestasis syndrome, and the other, fetal hydrops. PLoS One 8:e75770
Rook, Michelle; Vargas, Juan; Caughey, Aaron et al. (2012) Fetal outcomes in pregnancies complicated by intrahepatic cholestasis of pregnancy in a Northern California cohort. PLoS One 7:e28343
Bull, Laura N; Mahmoodi, Venus; Baker, Alastair J et al. (2006) VPS33B mutation with ichthyosis, cholestasis, and renal dysfunction but without arthrogryposis: incomplete ARC syndrome phenotype. J Pediatr 148:269-71
Fruhwirth, Martin; Janecke, Andreas R; Muller, Thomas et al. (2003) Evidence for genetic heterogeneity in lymphedema-cholestasis syndrome. J Pediatr 142:441-7
Bull, Laura N (2002) Hereditary forms of intrahepatic cholestasis. Curr Opin Genet Dev 12:336-42