Abstract 920: An N-ethyl-N-nitrosourea Mutagenesis Screen Identifies the Proximal End of Chromosome 1 as a Candidate Region for Murine Cardiomyopathy
N-ethyl-N-nitrosourea (ENU) mutagenesis in the mouse is a powerful tool to create novel mutations. Using this approach, mutations are generated at random across the genome and offspring are screened for phenotypes of interest. We have performed a recessive mutagenesis screen in adult mice to identify novel disease-causing genes for human heart failure. Using non-invasive echocardiography to screen for abnormalities in cardiac function, we have identified a heritable cardiomyopathic phenotype in several families. We have started to map the gene responsible for the cardiac phenotype in one family with 14 affected siblings. To identify the chromosomal region where the mutation is localized, we used a single nucleotide polymorphism (SNP) panel for genetic mapping of mouse mutations. The panel contained 318 informative SNPs between C57BL/6 and DBA/2J, the strains in our study. This panel provided whole genome linkage information and identified the mutagenized candidate region delimited from 6.2 Mb to 34.8 Mb at the proximal end of chromosome (chr) 1. Importantly, two of the 14 G3 progeny (ENX 261 and ENX 2533) have allowed us to narrow the interval to ~11 Mb (13.4 Mb - 24.6 Mb) using microsatellite markers and additional SNPs (see the table⇓). This interval is defined by the markers D1Mit64 and D1Mit520. The syntenic region of this interval is localized to chr 8 (71.7 Mb - 75.8 Mb) and chr 6 (50 Mb - 71.6 Mb) in humans. Interestingly, the syntenic region on chr 6 (6q12–16) was identified in a French family with 9 individuals affected by a pure form of autosomal dominant dilated cardiomyopathy. Some of the genes found in the mapped region on chr 1 are: musculin, junctophilin 1, and collagen alpha 1 (IX) chain precursor. A recessive ENU mutagenesis screen has allowed us to map a chromosomal region associated with dilated cardiomyopathy. Since we have identified the G2’s that carry the mutated allele, the rapid addition of affected progeny will allow us to positionally clone the responsible gene.