Thrombocytopenia And Cardiomyopathy (Trac): A New Single Gene Mutation Resulting In Severe Platelet And Heart Abnormalities In Mice.

We have discovered a new spontaneous mouse mutation, named “ thrombocytopenia and cardiomyopathy” ( trac ), in a colony of A/J mice at The Jackson Laboratory. Homozygosity for this recessive mutation results in severe pathologic changes in platelets, dilated cardiomyopathy, and infertility. Although platelet counts in A/J- trac/trac mice are normal at 3 weeks of age, there is a precipitous drop in platelet numbers and increases in platelet volumes by 4 weeks of age. Quantitative analyses of peripheral blood in A/J- trac/trac mice at 10 weeks of age showed a 20-fold reduction in platelet numbers accompanied by a 3-fold increase in platelet volumes compared with non-mutant (+/?) sex-matched controls. Other abnormalities in trac/trac platelets include greatly increased size of the microtubule coil and increased CD41 expression. Thrombocytopenia in trac/trac mice was associated with greatly increased bleeding times. Homozygotes ( trac/trac ) showed other hematological changes that included mild microcytic anemia accompanied by a doubling of reticulocyte numbers and two-fold decrease in WBC counts. Histological examination of blood smears confirmed abnormally enlarged platelets as well as the presence of megakaryocytoid cells. Increased numbers of megakaryocytes were present in BM, spleen, and lungs of trac/trac mice. Ultrastructural studies showed a lack of well-defined demarcation channels in trac/trac megakaryocytes. In order to determine whether the trac/trac platelet abnormality is intrinsic to defects at the level of BM progenitor cells, reciprocal BM chimeras were examined. Lethally irradiated +/+ recipients of 5 x 106 trac/trac BM cells were reconstituted with normal platelet numbers and volumes. In contrast, lethally irradiated trac/trac recipients of 5 x 106 +/+ BM cells remained thrombocytopenic. Backcrossing of the trac mutation onto the BALB/cBy strain background facilitated the identification of homozygotes prior to weaning and indicated the presence of modifying genes. Our preliminary data has produced a fine structure map of a 5 megabase interval containing the trac locus on mouse Chromosome 17. The human synteneic region is Chr 2p21-p22. We hypothesize that identification of the molecular basis of this mutation will reveal a novel gene that plays a critical role in the homeostasis of platelets and cardiomyocytes.