Identification of quantitative trait loci that modify the severity of hereditary spherocytosis in wan, a new mouse model of band-3 deficiency.
Document Type
Article
Publication Date
2004
Keywords
Base-Sequence, Blood-Proteins, Codon-Terminator, Crosses-Genetic, DNA, Disease-Models-Animal, Erythrocyte-Indices, Human, Lod-Score, Mice, Mice-Inbred-C3H, Mice-Mutant-Strains, Phenotype, Quantitative-Trait-Loci, Spectrin, Spherocytosis-Hereditary
First Page
3233
Last Page
3240
JAX Source
Blood 2004 Apr; 103(8):3233-40.
Abstract
Defects 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. Homozygous wan mice 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 in wan/wan mice from an F2 intercross between C3H/HeJ(+/wan) and CAST/Ei(+/+) F1 hybrids. Hematologic and survival data from C3H, CAST/Ei F2 wan homozygotes 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 (hereditary spherocytosis modifier 1), localizes to mouse Chromosome 12 and is dominant. The peak LOD score was obtained with a marker for Spnb1 encoding erythroid beta-spectrin, an obvious candidate gene.
Recommended Citation
Peters LL,
Swearingen RA,
Andersen SG,
Gwynn B,
Lambert AJ,
Li R,
Lux SE,
Churchill GA.
Identification of quantitative trait loci that modify the severity of hereditary spherocytosis in wan, a new mouse model of band-3 deficiency. Blood 2004 Apr; 103(8):3233-40.