The Ephx1(d) allele encoding an Arg338Cys substitution is associated with heat lability.
ABSTRACT Heat lability of the mouse hepatic microsomal epoxide hydrolase 1 enzyme-specific activity (EC 184.108.40.206) is greater for the A/J than the C57BL/6J strain. Analysis of the microsomal epoxide hydrolase 1 cDNA coding sequences shows the C57BL/6J and A/J strains to differ in a single base, a C to T transition at position 1012 from the ATG. This change would predict a substitution of an Arg for a Cys at codon 338. Lyman et al. (J. Biol. Chem 255:8650, 1980) studied 26 inbred mouse strains and assigned each strain to one of two groups based upon functional criteria that included heat lability and pH optima for microsomal epoxide hydrolase 1. The heat-labile strains including A/J were denoted with the Ephx1(d) allele, whereas C57BL/6J and other members of the heat-stable strains were denoted with the Ephx1(b) allele. We examined those same inbred mouse strains and found complete concordance between the assignment of microsomal epoxide hydrolase 1 allele superscript "b" or "d" and the wild-type and C1012T polymorphism respectively (Fisher's Exact Test, two-sided p < 0.0001). These data suggest that mouse hepatic microsomal epoxide hydrolase 1 heat lability is associated with the presence of a Cys at residue 338. Genomic samples from the available AXB and BXA recombinant inbred strains were allelotyped for the SNP identified in the Ephx1 gene that distinguishes the A/J and C57BL/6J parental strains and used to map Ephx1 to Chromosome (Chr) 1 at approximately 98.5cM (LOD = 10.0).
SourceAvailable from: Nicole A R Walter[Show abstract] [Hide abstract]
ABSTRACT: We report here the confirmation of the quantitative trait locus for haloperidol-induced catalepsy on distal chromosome (Chr) 1. We determined that this quantitative trait locus was captured in the B6.D2-Mtv7a/Ty congenic mouse strain, whose introgressed genomic interval extends from approximately 169.1 to 191.3 Mb. We then constructed a group of overlapping interval-specific congenic strains to further break up the interval and remapped the locus between 177.5 and 183.4 Mb. We next queried single nucleotide polymorphism (SNP) data sets and identified three genes with nonsynonymous coding SNPs in the quantitative trait locus. We also queried two brain gene expression data sets and found five known genes in this 5.9-Mb interval that are differentially expressed in both whole brain and striatum. Three of the candidate quantitative trait genes were differentially expressed using quantitative real-time polymerase chain reaction analyses. Overall, the current study illustrates how multiple approaches, including congenic fine mapping, SNP analysis and microarray gene expression screens, can be integrated both to reduce the quantitative trait locus interval significantly and to detect promising candidate quantitative trait genes.Genes Brain and Behavior 04/2008; 7(2):214-23. DOI:10.1111/j.1601-183X.2007.00340.x · 3.51 Impact Factor