The mouse pink-eyed unstable (p"a) mutation, affecting coat color, exhibits one of the highest reported reversion frequencies of any mammalian mutation and is associated with a duplication of genomic DNA at thep locus. In this study, genomic clones containing the boundaries of thep" dupliation were isolated and characterized. The stru of these sequences and their wild-type and revertant counterparts were analyzed by restriction mapping, PCR product analysis, DNA sequence analysis, and pulsed-field gel electrophoresis. DNA from p"" was distnguhed from wild-type and revertant DNA by a head-to-tail tandem duplication of w7O kilobases. No differences were detected between revertant and wild-type DNAs. Thus, the reversion in phenotype of pr" mice is coupled with the loss ofone copy of an -70-kilobase duplicated segment.Testable models are presented to account for pa" reversion.
Thrombosis is a life-threatening complication of hemolytic anemia in humans. Cardiac thrombi are present in all adult ␣-spectrin-deficient (sph/sph) mice with severe hereditary spherocytosis, providing a model for events preceding thrombosis. The current study evaluated (1) the timing of thrombosis initiation and (2) the effect of postnatal transplantation of normal cells on life span and thrombotic incidence in adult mice. Thrombi are detected histologically following necropsy in untreated sph/sph mice of various ages and are not observed until 6 weeks of age. Thrombotic incidence increases from 50% at 6 to 7 weeks of age to 100% at 9 weeks of age. As a potential therapy, nonablated sph/sph neonates were transfused with either genetically marked normal peripheral blood (PB), bone marrow (BM) ,
IntroductionOne of the more serious complications of heritable hemolytic anemias in humans is thrombosis. Thrombotic events affect approximately 20% of patients with sickle cell disease, 5% to 10% of patients with -thalassemia, and a small number of patients with hereditary spherocytosis (HS). [1][2][3][4][5][6][7][8][9][10] In adult mice with severe hemolytic anemia caused by deficiency of red blood cell (RBC) cytoskeletal components, cardiac thrombi are prevalent. 11,12 The mutant mice have severe HS typified by misshapen RBCs that are destroyed within a single day of entry into the peripheral blood (PB). 11 Reticulocytes compose 75% to 95% of the total circulating erythroid cells; mean cell volume (MCV) is increased, reflecting the larger, immature cells in the circulation. [13][14][15] Spleen and liver, sources of newly generated RBCs in anemic mice, are grossly enlarged. [13][14][15] Iron deposits accumulate in the kidney and liver. 11 Mice with HS are much more severely affected than most humans with HS, many of whom are not diagnosed until an unrelated health crisis arises.There are few models for thrombosis in experimental animals with hemolytic anemia. The mice with HS adequately fill that void. The incidence of coronary thrombosis is highest (85% to 100%) in HS mice with mutations in ␣-spectrin (Spna1), and lowest (15% to 22%) in HS mice with -spectrin and ankyrin mutations. 11,12 These mice, except for the mutation they carry, share identical genetic backgrounds and environments, permitting comparative analyses. Adult Spna1 sph / Spna1 sph (hereafter, sph/sph) mice have the highest incidence (100%) of thrombosis. They provide a model for determining thrombus ontogeny, pathological consequences, precipitating agents, and efficacy of therapeutic interventions. Death of 30% of untreated sph/sph mice occurs before 3 weeks of age; the average life span of the survivors is 26.8 weeks. It is not clear whether the postnatal deaths are caused by thrombosis or other pathology. Here, the temporal development of thrombosis is established in sph/sph mice.To date, we have shown that bone marrow (BM) hematopoietic cells transplanted from sph/sph mice to normal recipients are sufficient for thrombogenesis 12 and that inversi...
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