International Mammalian Genome Society

The 14th International Mouse Genome Conference (2000)

B16. A Novel Waved Mutant Mouse Develops Dilated Cardiomyopathy

BJ Herron, L Pacella, C. Semsarian, C. Seidman, C Rao, L Stubbs1, S Millar2, DR Beier
Genetics Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
Lawrence Livermore National Laboratory;
Department of Dermatology, University of Pennsylvania, Philadelphia, PA

We have discovered a novel recessive mutation affecting skin, hair, and heart development in mice. Mutant mice have open eyes at birth and develop a coat that appears wavy. This phenotype is nearly identical to that seen in the mutations waved 1 (wa1) and waved 2 (wa2). Hearts of 3-week-old mice are abnormally shaped and have focal fibrosis histologically. Older mice (4-6 months) have dilated cardiomyopathy and show extensive fibrosis. Echocardiograms were consistent with these observations. Left ventricular ejection fractions were 13% in mutant mice, compared to 58% in normal littermates of similar age.

We have analyzed an intercross that localized this phenotype to proximal mouse Chr. 7. Therefore, this mutation is not allelic with either wa1 or wa2, which map to Chr. 6 and 11 respectively, and we have designated it as waved 3 (wa3). The wa3 non-recombinant interval has conserved homology with human chromosome 19q13.2. The human genomic DNA corresponding to this interval has been completely sequenced and we have identified mouse BACs that cover the wa3 interval. Together, these reagents have provided several candidates that we are analyzing in mutant mice.

The genes affected in wa1 and wa2 mice have been identified. Transforming Growth Factor alpha (Tgfa) is a widely expressed growth factor that is under-expressed in wa1/wa1 mice. Epidermal growth factor receptor (Egfr), the receptor for the Tgfa protein, is mutated in wa2/wa2 mice. This ligand/receptor pathway has been investigated extensively; however, little is known about other genes that participate in the signaling process. While wa3 has not been proven to participate in this pathway, the phenotype is strikingly similar to wa1 and wa2 and we propose that the wa3 mutation is in a gene that is a member of the Tgfa signal cascade.

The striking dilated cardiomyopathy seen in these mice has not been fully characterized; however, preliminary studies suggest there may be an intrinsic defect in heart muscle function. Recent studies have indicated that wa2 mice also have a valvular cardiac defect that can be exacerbated by an epistatic interaction with Shp2. Molecular characterization of the mutation in the wa3 mice should clarify the potential role of the causal gene(s) in Tgfa signaling and cardiac development.

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