This H794L point substitution in the C terminus domain of the RASA3 GTPas-activating protein causes leukopenia, splenomegaly due to a large increase in megakaryocytes in the red pulp, and thrombocytopenia due to faster platelet turnover, but the hematocrit and red blood cell counts are normal. This is a very mild phenotype compared with the prenatal and perinatal lethality that occurs in Rasa3 null homozygotes and a somewhat less severe phenotype than that caused by the Rasa3scat mutation. This mutant may provide a model for studying some aspects of aplastic anemia.Read More +
This hypomorphic mutation was initially identified in a phenotypic screen of third generation mice (G3) from ENU mutagenized males. A 6-week-old male (born 1/7/2004) maintained on standard chow was found to have a platelet count of 24 x 103 cells/ul, which is approximately 98% lower than controls. One sibling was similarly affected. RASA3 is a RAS and RAP1 GTPase-activating protein that moves between the cytosol and the plasma membrane and when localized to the platelet plasma membrane it inhibits platelet activation in homeostatic balance against RASGRP2. This ENU-induced point mutation causes an H794L substitution in the C terminus domain which results in a reduction of RASA3 expression in homozygotes and loss of GAP activity. Stefanini et al. reported that heterozygous intercrosses generate the normal Mendelian ratio of mutants with higher platelet counts than those found in mice homozygous for the scat or null mutations, consistent with this being a less severe phenotypic allele. The mean platelet volume was reported to be much larger than normal and the white blood cell count significantly lower, but the hematocrit and red blood cell counts were not found to be significantly abnormal. Heterozygotes were found to have normal platelet and leukocyte counts, but Rasa3hlb381/scat compound heterozygotes displayed severe thrombocytopenia. The half-life for circulating platelets in Rasa3hlb381 homozygotes was found to be only 14 hours compared with 55 hours in wildtype controls, these platelets have increased activated RAP1-GTP and activated alphaIIBeta3 integrin and the number of reticulated (immature) platelets was more than 3 times higher than normal, indicative of a high rate of both platelet destruction and production of new platelets. There is a significant increase in the number of megakaryocytes in the bone marrow and splenic red pulp, to the extent that it results in splenomegaly. This is all consistent with reduced platelet survival/increased clearance and rate of platelet production to compensate for the continued loss.
Following multidose ethylnitrosourea (ENU) treatments to induce mutations in male founder C57BL/6J mice (Stock No. 000664), a forward genetic screen was utilized to identify phenotypic deviants in complex heart, lung, blood, and sleep disorders, at the Mouse Heart, Lung, Blood, and Sleep Disorders (HLBS) Center at The Jackson Laboratory. hlb381 was mapped to Chromosome 8 and later determined to be a H794L mutation in Rasa3. This mutation was maintained coisogenic on C57BL/6J and sibling intercrossed to homozygosity. Embryos were generated from homozygous females crossed to homozygous males at generations N3F4 through N3F6.
|Allele Name||heart, lung and blood 381|
|Allele Type||Chemically induced (ENU) (Hypomorph)|
|Allele Synonym(s)||Rasa3H794L; Rasa3hlb|
|Gene Symbol and Name||Rasa3, RAS p21 protein activator 3|
|Strain of Origin||C57BL/6J|
|Molecular Note||ENU mutagenesis induced an A to T point mutation that results in the amino acid substitution of leucine for histidine at position 794 (H794L) and reduced expression of the protein is found in platelets from homozygotes but not heterozygotes.|
This strain can be maintained by intercrossing homozygotes.
When using the HLB381 mouse strain in a publication, please cite the originating article(s) and include JAX stock #005343 in your Materials and Methods section.
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