We have investigated spectrin synthesis and mRNA activity in mice homozygous and heterozygous for six mutations occurring at three distinct loci (nb, ja, sph). When homozygous, these mutations cause severe hemolytic anemias that are characterized by specific spectrin deficiencies. Our results indicate that the primary effect of the nb mutation is a deficiency of another erythrocyte membrane skeletal protein, ankyrin. The severe deficiency of spectrin in the red blood cells of ja/ja mice is the result of a beta spectrin defect. Analysis of spectrin synthesis in mice homozygous and heterozygous for several alleles of sph indicates that the sph locus is the structural gene locus for alpha spectrin. We have mapped the sph locus to mouse Chromosome 1.