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Mammalian Genome

, Volume 20, Issue 5, pp 296–304 | Cite as

An N-ethyl-N-nitrosourea mutagenesis recessive screen identifies two candidate regions for murine cardiomyopathy that map to chromosomes 1 and 15

  • Liliana Fernandez
  • Douglas A. Marchuk
  • Jennifer L. Moran
  • David R. Beier
  • Howard A. Rockman
Article

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.

Keywords

Dilate Cardiomyopathy Emerin Mutagenesis Screen Phenotypic Screen Conscious Mouse 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We thank Lan Mao, Kristine Porter, and Barbara Williams for their outstanding technical assistance. This research was funded by an American Heart Association Postdoctoral Fellowship 0625436U to LF, U01 HD43430 to DB, and the National Institutes of Health grant HL083065 to HAR.

Supplementary material

335_2009_9184_MOESM1_ESM.pdf (42 kb)
Supplementary material 1 (PDF 43 kb)
335_2009_9184_MOESM2_ESM.pdf (29 kb)
Supplementary material 1 (PDF 30 kb)

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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Liliana Fernandez
    • 1
  • Douglas A. Marchuk
    • 2
  • Jennifer L. Moran
    • 3
  • David R. Beier
    • 4
  • Howard A. Rockman
    • 1
    • 2
  1. 1.Department of MedicineDuke University Medical CenterDurhamUSA
  2. 2.Department Molecular Genetics and MicrobiologyDuke University Medical CenterDurhamUSA
  3. 3.Genetic Analysis PlatformBroad Institute of MIT and HarvardCambridgeUSA
  4. 4.Division of GeneticsBrigham & Women’s Hospital and Harvard Medical SchoolBostonUSA

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