MSH3 polymorphisms and protein levels affect CAG repeat instability in huntington's disease mice

Expansions of trinucleotide CAG/CTG repeats in somatic tissues are thought to contribute to ongoing disease progression through an affected individual's life with Huntington's disease or myotonic dystrophy. Broad ranges of repeat instability arise between individuals with expanded repeats, suggesting the existence of modifiers of repeat instability. Mice with expanded CAG/CTG repeats show variable levels of instability depending upon mouse strain. However, to date the genetic modifiers underlying these differences have not been identified. We show that in liver and striatum the R6/1 Huntington's disease (HD) (CAG)~100 transgene, when present in a congenic C57BL/6J (B6) background, incurred expansion-biased repeat mutations, whereas the repeat was stable in a congenic BALB/cByJ (CBy) background. Reciprocal congenic mice revealed the Msh3 gene as the determinant for the differences in repeat instability. Expansion bias was observed in congenic mice homozygous for the B6 Msh3 gene on a CBy background, while the CAG tract was stabilized in congenics homozygous for the CBy Msh3 gene on a B6 background. The CAG stabilization was as dramatic as genetic deficiency of Msh2. The B6 and CBy Msh3 genes had identical promoters but differed in coding regions and showed strikingly different protein levels. B6 MSH3 variant protein is highly expressed and associated with CAG expansions, while the CBy MSH3 variant protein is expressed at barely detectable levels, associating with CAG stability. The DHFR protein, which is divergently transcribed from a promoter shared by the Msh3 gene, did not show varied levels between mouse strains. Thus, naturally occurring MSH3 protein polymorphisms are modifiers of CAG repeat instability, likely through variable MSH3 protein stability. Since evidence supports that somatic CAG instability is a modifier and predictor of disease, our data are consistent with the hypothesis that variable levels of CAG instability associated with polymorphisms of DNA repair genes may have prognostic implications for various repeat-associated diseases

Blood Meal Preference of Some Anopheline Mosquitoes in Command and Non-command Areas of Rajasthan, India

Background: The present study was undertaken to compare the entomological situation by analyzing the bloodmeal of mosquitoes of canal irrigated and non-irrigated areas of Bikaner in order to explore scientific information onthe vector biology and malaria burden profile and to plan proper strategies for malaria control and eradication.Methods: Adult mosquitoes were collected and the abdomen of the blood fed females were crushed on a filter paperfor blood meal analysis and subjected to precipitin test.Results: The blood meal analysis showed that Anopheles subpictus had a preference towards cattle blood, An.culicifacies and An. stephensi preferred human blood, while, An. annularis was noted to feed only on bovine blood.Conclusion: Although An. annularis, has been recently reported from the area, was found to feed exclusively onbovine blood, earlier reports suggest that this species is a vector of malaria and therefore preventive measuresshould be taken well in advance before this species gets established in the area