Spherocytosis, Type 4

A number sign (#) is used with this entry because spherocytosis type 4 (SPH4) is caused by heterozygous mutation in the band 3 gene (SLC4A1, EPB3; 109270) on chromosome 17q21.

For a general description and a discussion of genetic heterogeneity of spherocytosis, see SPH1 (182900).

Clinical Features

Prchal et al. (1991) studied a family with autosomal dominant hereditary spherocytosis associated with deficiency of erythrocyte band 3 protein.

Del Giudice et al. (1992) reported a family in which a dominantly inherited form of hereditary spherocytosis was associated with deficiency of band 3, resulting in an increased spectrin/band 3 ratio. Since deficiency of spectrin is a much more frequent cause of hereditary spherocytosis, the usual finding is a decreased spectrin/band 3 ratio. An increased spectrin/band 3 ratio, pointing to a band 3 defect, was found in 2 families with hereditary spherocytosis studied by Lux et al. (1990).

Del Giudice et al. (1993) described a family in which both hereditary spherocytosis due to band 3 deficiency and beta-0-thalassemia trait due to codon 39 (C-T) mutation (141900.0312) were segregating. Two subjects with HS alone had a typical clinical form of spherocytosis with anemia, reticulocytosis, and increased red cell osmotic fragility. Two who coinherited HS and beta-thalassemia trait were not anemic and showed a slight, well-compensated hemolysis. Thus, the beta-thalassemic trait partially corrected or 'silenced' HS caused by band 3 deficiency.

Pathogenesis

Saad et al. (1991) examined the mechanism underlying band 3 deficiency in a subset of patients with hereditary spherocytosis.

Mapping

Prchal et al. (1991) performed linkage analysis in a family with autosomal dominant hereditary spherocytosis associated with deficiency of erythrocyte band 3 protein. They excluded linkage with alpha-spectrin (182860), beta-spectrin (182870), and ankyrin (612641), but found a suggestion of linkage to EPB3 (SLC4A1). They used RFLPs not only in the EPB3 gene but also in the NGFR gene (162010) which, like EPB3, maps to 17q21-q22. A maximum lod score of 11.40 at theta = 0.00 was observed. Study of 42 members from 4 generations revealed a consistent linkage of spherocytosis with 1 particular haplotype generated by the 4 probes that were used.

Molecular Genetics

In a 28-year-old female with congenital spherocytic hemolytic anemia, Jarolim et al. (1991) identified a missense mutation in the band 3 gene (109270.0003).

In a 33-year-old woman with pregnancy-associated hemolytic anemia and spherocytosis, Rybicki et al. (1993) identified a G40K mutation in band 3 (109270.0004).

In a 3-generation Czech family in which 5 affected members exhibited compensated hemolytic disease, Jarolim et al. (1994) identified a 10-bp duplication in the SLC4A1 gene (109270.0005) that segregated with disease. Before splenectomy, affected individuals had reticulocytosis, hyperbilirubinemia, and increased osmotic fragility.

In affected members of a large Swiss family with spherocytosis, Maillet et al. (1995) identified heterozygosity for a G771D mutation in band 3 (109270.0007).

In an 18-year-old French man with moderate hereditary spherocytosis, Alloisio et al. (1996) identified an R150X mutation in band 3 (109270.0009). The proband's mother, who also carried the mutation, had a milder clinical presentation. Further investigation revealed a second, paternally inherited band 3 mutation in the proband (109270.0010).

Eber et al. (1996) found that band 3 frameshift and nonsense null mutations occurred in dominant hereditary spherocytosis. In studies of 46 HS families, 12 ankyrin-1 (612614) mutations and 5 band 3 mutations were identified.

Among 80 hereditary spherocytosis kindreds studied using denaturing electrophoretic separation of solubilized erythrocyte membrane proteins, Dhermy et al. (1997) recognized 3 prominent subsets: HS with isolated spectrin deficiency, HS with combined spectrin and ankyrin deficiency, and HS with band 3 deficiency. These 3 subsets represented more than 80% of the HS kindreds studied. In 8 dominant HS kindreds with band 3 deficiency mutations were sought. In each, linkage analysis confirmed the band 3 gene as the culprit gene. Five different mutations were found in the 8 kindreds. Dhermy et al. (1997) found that the amount of band 3 appeared to be slightly, but significantly, more reduced in HS patients with missense mutations and presence of the mutant transcripts than in HS patients with premature termination of translation and absence of mutant transcripts. This led to speculation that missense mutations may have a dominant negative effect.

In a 29-year-old Japanese man with compensated hemolytic anemia and spherocytosis, Inoue et al. (1998) identified homozygosity for an SLC4A1 G130R mutation (109270.0018).

In a 22-year-old Japanese man who presented with cholelithiasis and hemolysis and had a history of jaundice since early childhood, Iwase et al. (1998) identified a T837A mutation in SLC4A1 (109270.0019).

Bruce et al. (2005) identified 11 human pedigrees with dominantly inherited hemolytic anemias in both the hereditary stomatocytosis (see 185020) and spherocytosis classes. Affected individuals in these families had an increase in membrane permeability to sodium and potassium ion that was particularly marked at zero degree centigrade. They found that disease in these pedigrees was associated with a series of single amino acid substitutions in the intramembrane domain of the band 3 anion exchanger, AE1. Anion movements were reduced in the abnormal red cells. The 'leak' cation fluxes were inhibited by chemically diverse inhibitors of band 3. Expression of the mutated genes in Xenopus laevis oocytes induced abnormal NA and K fluxes in the oocytes, and the induced chloride transport was low. These data were considered consistent with the suggestion that the substitutions convert the protein from an anion exchanger into an unregulated cation channel. Only 1 of the gene changes, R760Q (109270.0028), had previously been reported (Jarolim et al., 1995). All the mutations were in exon 17 of the AE1 gene.