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 15;103(8):3233-40. doi: 10.1182/blood-2003-08-2813. Epub 2003 Dec 30.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anion Exchange Protein 1, Erythrocyte / deficiency*
  • Anion Exchange Protein 1, Erythrocyte / genetics*
  • Base Sequence
  • Blood Proteins / deficiency
  • Codon, Terminator
  • Crosses, Genetic
  • Cytoskeletal Proteins
  • DNA / genetics
  • Disease Models, Animal
  • Erythrocyte Indices / genetics
  • Humans
  • Lod Score
  • Membrane Proteins
  • Mice
  • Mice, Inbred C3H
  • Mice, Mutant Strains
  • Phenotype
  • Quantitative Trait Loci*
  • Spectrin / genetics
  • Spherocytosis, Hereditary / blood*
  • Spherocytosis, Hereditary / genetics*


  • Anion Exchange Protein 1, Erythrocyte
  • Blood Proteins
  • Codon, Terminator
  • Cytoskeletal Proteins
  • Membrane Proteins
  • erythrocyte membrane band 4.2 protein
  • Spectrin
  • DNA