title: An N-ethyl-N-nitrosourea mutagenesis recessive screen identifies two candidate regions for murine cardiomyopathy that map to chromosomes 1 and 15.
abstract: N-ethyl-N-nitrosourea (ENU) mutagenesis screens have been successful for identifying genes that affect important biological processes and diseases. However, for heart-related phenotypes, these screens have been employed exclusively for developmental phenotypes, and to date no adult cardiomyopathy-causing genes have been discovered through a mutagenesis screen. To identify novel disease-causing and disease-modifying genes for cardiomyopathy, we performed an ENU recessive mutagenesis screen in adult mice. Using noninvasive echocardiography to screen for abnormalities in cardiac function, we identified a heritable cardiomyopathic phenotype in two families. To identify the chromosomal regions where the mutations are localized, we used a single nucleotide polymorphism (SNP) panel for genetic mapping of mouse mutations. This panel provided whole-genome linkage information and identified the mutagenized candidate regions at the proximal end of chromosome 1 (family EN1), and at the distal end of chromosome 15 (family EN25). We have identified 94 affected mice in family EN1 and have narrowed the candidate interval to 1 Mb. We have identified 20 affected mice in family EN25 and have narrowed the candidate interval to 12 Mb. The identification of the genes responsible for the observed phenotype in these families will be strong candidates for disease-causing or disease-modifying genes in patients with heart failure.
authors.affiliation: Department of Medicine, Duke University Medical Center, DUMC, Durham, NC 27710, USA.
authors.forename: Liliana
authors.initials: L
authors.lastname: Fernandez
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Marchuk
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Moran
authors.forename: David R
authors.initials: DR
authors.lastname: Beier
authors.forename: Howard A
authors.initials: HA
authors.lastname: Rockman
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics* / Q000503:physiopathology; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics*; D004195:Disease Models, Animal; D005038:Ethylnitrosourea; D005260:Female; D005808:Genes, Recessive; D005820:Genetic Testing; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016296:Mutagenesis; D009153:Mutagens
chemical_list: D009153:Mutagens; D005038:Ethylnitrosourea