title: A post-developmental genetic screen for zebrafish models of inherited liver disease.
abstract: Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease such as simple steatosis, nonalcoholic steatohepatitis (NASH), cirrhosis and fibrosis. However, the molecular pathogenesis and genetic variations causing NAFLD are poorly understood. The high prevalence and incidence of NAFLD suggests that genetic variations on a large number of genes might be involved in NAFLD. To identify genetic variants causing inherited liver disease, we used zebrafish as a model system for a large-scale mutant screen, and adopted a whole genome sequencing approach for rapid identification of mutated genes found in our screen. Here, we report on a forward genetic screen of ENU mutagenized zebrafish. From 250 F2 lines of ENU mutagenized zebrafish during post-developmental stages (5 to 8 days post fertilization), we identified 19 unique mutant zebrafish lines displaying visual evidence of hepatomegaly and/or steatosis with no developmental defects. Histological analysis of mutants revealed several specific phenotypes, including common steatosis, micro/macrovesicular steatosis, hepatomegaly, ballooning, and acute hepatocellular necrosis. This work has identified multiple post-developmental mutants and establishes zebrafish as a novel animal model for post-developmental inherited liver disease.
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, the United States of America.
authors.forename: Seok-Hyung
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Biology, Vanderbilt University, Nashville, TN, 37232, the United States of America.
authors.forename: Shu-Yu
authors.initials: SY
authors.lastname: Wu
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, the United States of America.
authors.forename: Jeong-In
authors.initials: JI
authors.lastname: Baek
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, the United States of America.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Choi
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, the United States of America.
authors.forename: Yanhui
authors.initials: Y
authors.lastname: Su
authors.affiliation: Department of Surgery, Vanderbilt University, Nashville, TN, 37232, the United States of America.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Flynn
authors.affiliation: Department of Biology, Vanderbilt University, Nashville, TN, 37232, the United States of America.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Gamse
authors.affiliation: Department of Pediatrics, Vanderbilt University, Nashville, TN, 37232, the United States of America.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Ess
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, the United States of America.
authors.forename: Gary
authors.initials: G
authors.lastname: Hardiman
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, the United States of America; Department of Medicine, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, 29401, the United States of America.
authors.forename: Joshua H
authors.initials: JH
authors.lastname: Lipschutz
authors.affiliation: Department of Surgery, Vanderbilt University, Nashville, TN, 37232, the United States of America.
authors.forename: Naji N
authors.initials: NN
authors.lastname: Abumrad
authors.affiliation: Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, the United States of America.
authors.forename: Don C
authors.initials: DC
authors.lastname: Rockey
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005038:Ethylnitrosourea / Q000633:toxicity; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D006801:Humans; D008099:Liver / Q000473:pathology; D009154:Mutation; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000473:pathology*; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development*
chemical_list: D005038:Ethylnitrosourea