Cholestasis (impairment of bile flow) is a common and often devastating manifestation of both acquired and inherited liver disease. However, the biology of normal bile formation and bile acid secretion are poorly understood, as is the pathophysiology of cholestasis. The goal of the proposed studies is to identify and functionally characterize the gene(s) responsible for two distinct, autosomal recessive, inherited cholestatic disorders: benign recurrent intrahepatic cholestasis (BRIC) and progressive familial intrahepatic cholestasis (PFIC), also commonly called Byler's syndrome after the originally described kindred. This proposal builds upon extensive preliminary studies, which include (a) development of a novel approach for localization of abnormal gene(s) in inbred populations that uses linkage disequilibrium (LD) between alleles of polymorphic DNA markers and the disease allele to identify conserved chromosomal segments harboring the disease gene(s), (b) use of this approach to map the gene(s) responsible for both BRIC and PFIC to a small (approximately 6 centiMorgan) region on chromosome 18, making it highly likely that the BRIC and PFIC genes are identical, and (c) development of probes for novel hepatic ATP-binding cassette proteins postulated to mediate hepatic bile acid secretion and to represent the abnormal gene in both disorders. The proposed studies will use a variety of genetic and physical mapping methods to identify the disease gene(s) and corresponding cDNA(s), including screening for chromosome rearrangements, to enable evaluation of candidate cDNAs from the smallest possible region. These cDNAs will then be used to screen patient genomic DNA for mutations and mRNA for altered patterns of expression. Following its definitive identification the function of the causative gene will be defined by examining the relationship between different mutations and disease phenotypes characterizing its function heterologous expression of the cDNA(s), and construction of a mouse model (i.e., knockout model) in which a mutant copy of the gene has been introduced. The proposed studies will provide important new insight into the biology of bile secretion and pathophysiology of cholestasis and are anticipated to lead to new approaches to the diagnosis and treatment for inherited and acquired liver diseases.
| Shah, Sohela; Sanford, Ukina R; Vargas, Julie C et al. (2010) Strain background modifies phenotypes in the ATP8B1-deficient mouse. PLoS One 5:e8984 |
| Pawlikowska, Ludmila; Strautnieks, Sandra; Jankowska, Irena et al. (2010) Differences in presentation and progression between severe FIC1 and BSEP deficiencies. J Hepatol 53:170-8 |
| Strautnieks, Sandra S; Byrne, Jane A; Pawlikowska, Ludmila et al. (2008) Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families. Gastroenterology 134:1203-14 |
| Knisely, A S; Strautnieks, Sandra S; Meier, Yvonne et al. (2006) Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency. Hepatology 44:478-86 |
| Paulusma, Coen C; Groen, Annemiek; Kunne, Cindy et al. (2006) Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport. Hepatology 44:195-204 |
| Klomp, Leo W J; Vargas, Julie C; van Mil, Saskia W C et al. (2004) Characterization of mutations in ATP8B1 associated with hereditary cholestasis. Hepatology 40:27-38 |
| van Mil, Saskia W C; van der Woerd, Wendy L; van der Brugge, Gerda et al. (2004) Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11. Gastroenterology 127:379-84 |
| Carlton, Victoria E H; Pawlikowska, Ludmila; Bull, Laura N (2004) Molecular basis of intrahepatic cholestasis. Ann Med 36:606-17 |
| Pawlikowska, Ludmila; Groen, Annemiek; Eppens, Elaine F et al. (2004) A mouse genetic model for familial cholestasis caused by ATP8B1 mutations reveals perturbed bile salt homeostasis but no impairment in bile secretion. Hum Mol Genet 13:881-92 |
| Bull, Laura N (2002) Hereditary forms of intrahepatic cholestasis. Curr Opin Genet Dev 12:336-42 |
Showing the most recent 10 out of 16 publications
