1. Genetic studies of Familial hypercholanemia (FHCA).
We have performed genetic mapping studies of this disorder in Amish families. Using only a small set of patients, in combination with highly efficient mapping techniques, we have identified mutations in 2 genes (TJP2 and BAAT) associated with FHCA in the Amish. Inheritance of FHC appears to be oligogenic, indicating that FHCA lies in the border zone between simple and complex genetic traits. We also have evidence suggesting a 3rd FHC locus exists in the Amish.

2. Study of disease caused by mutation in FIC1(ATP8B1), and characterization of mouse models of ATP8B1 disease.
ATP8B1 is a P-Type ATPase present in many tissues, and likely to function as an aminophospholipid flippase. Several years ago, I led a project resulting in its identification as the protein defective in two forms of hereditary liver disease differing in their severity. My laboratory currently pursues several strands of research on ATP8B1, including

a) Characterization of a mouse model of ATP8B1 disease.
We have generated a mouse carrying a mutation in Atp8b1. In a collaborative study, we have performed initial evaluation of the phenotype of this mouse. Our findings in this mouse model were unanticipated, as they indicate that, in the mouse model of ATP8B1 disease, the primary defect is in regulation of intestinal reabsorption of bile acids, rather than in transport of bile acids out of the liver. This finding suggests the novel hypothesis that excessive intestinal reabsorption of bile acids could contribute to development of liver disease in human patients. We have suggestive evidence that the phenotype of this mutant mouse may differ depending upon strain background, and if these findings are confirmed, we may pursue genetic mapping of modifier loci responsible for the inter-strain differences in phenotype.

b) Phenotype-genotype correlation studies in hereditary cholestasis.
We have performed large-scale mutation screening of patients with hereditary cholestasis, and are leading in a collaborative study in which we are comparing clinical, biochemical, histopathological, and treatment-outcome data in patients with liver disease due to ATP8B1 mutation and in patients whose liver disease is associated with mutation in ABCB11 (which encodes the hepatic bile salt export protein). The goals of this study are to enable more accurate clinical diagnosis of hereditary cholestasis, and prediction of treatment outcomes, and to increase our understanding of the biology of these genetically distinct disorders. A number of interesting and unanticipated findings are emerging from this study.

3. Genetic studies of lymphedema-cholestasis syndrome (LCS, Aagenaes syndrome).
In this disorder, patients typically suffer transient but severe liver disease early in life, and develop chronic lymphedema. Through study of Norwegian LCS patients using population genetic mapping techniques, we have mapped a locus for this disease to chromosome 15. We are performing high-resolution genetic mapping studies and evaluation of candidate genes to identify the mutated gene.

4. Evaluation of genetic factors influencing susceptibility to 'secondary' liver diseases, including drug-induced cholestasis.
It is likely that variants in some of the genes we and others have identified as being mutated in Mendelian liver disorders also affect susceptibility to more common, secondary forms of liver disease, such as intrahepatic cholestasis of pregnancy (ICP), steroid-induced cholestasis (including that induced by birth control pills), and cholestasis induced by surgery, sepsis, or non-steroidal drugs. We have begun collection of DNA from patients with ICP and steroid-induced cholestasis, as well as evaluation of candidate genes in these patients.