Abstract
AbstractDefects in red blood cell (RBC) membrane skeleton components cause hereditary spherocytosis (HS). Clinically, HS varies significantly even among individuals with identical gene defects, illustrating the profound effects of genetic background on disease severity. We exploited a new spontaneous mouse model,wan, which arose on the inbred C3H/HeJ strain, to identify quantitative trait loci (QTL) that modify the HS phenotype. Homozygouswanmice have severe HS due to a complete deficiency of erythroid band 3. A QTL analysis of RBC count, hemoglobin, hematocrit, mean corpuscular volume (MCV), and mean corpuscular hemoglobin content (MCHC) was performed inwan/wanmice from an F2 intercross between C3H/HeJ+/wanand CAST/Ei+/+F1 hybrids. Hematologic and survival data from C3H, CAST/Ei F2wanhomozygotes support the hypothesis that genetic modifiers significantly influence the band-3 null HS phenotype. Significant QTL were identified for the MCV trait only, suggesting that RBC membrane characteristics are a target for modifier gene action. The most significant quantitative trait locus,Hsm1(hereditaryspherocytosismodifier 1), localizes to mouse Chromosome 12 and is dominant. The peak LOD score was obtained with a marker forSpnb1encoding erythroid β-spectrin, an obvious candidate gene. (Blood. 2004;103: 3233-3240)
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