Elliptocytosis 2

A number sign (#) is used with this entry because of evidence that elliptocytosis-2 (EL2) is caused by heterozygous mutation in the alpha-spectrin gene (SPTA1; 182860) on chromosome 1q23.

For a general description and a discussion of genetic heterogeneity of elliptocytosis (HE), see EL1 (611804).

Clinical Features

In some families with HE, spectrin is abnormally heat-sensitive (Lux and Wolfe, 1980). Coetzer and Zail (1981) studied spectrin in 4 cases of hereditary elliptocytosis and found an abnormality of tryptic digestion in 1. This patient was previously reported by Gomperts et al. (1973) as an instance of hemolytic anemia due to HE.

Liu et al. (1982) examined erythrocytes from 18 patients with hereditary elliptocytosis. In 8 patients (referred to as type 1), spectrin was defective in dimer-dimer association as demonstrated in 2 ways. First, spectrin dimer was increased and tetramer decreased; spectrin dimer represented 15 to 33% of total spectrin compared with a normal range of 3 to 7%. Second, the equilibrium constants of spectrin dimer-dimer association was decreased in both solution and in situ in red cell membranes. In the other 10 patients (referred to as type 2), dimer-dimer association was normal. Membrane skeletons, produced from both types of elliptocytosis by Triton X-100 extraction of the red cell ghosts, were unstable when mechanically shaken. Spectrin tetramers but not dimers can crosslink actin.

Evans et al. (1983) studied a family in which 3 sibs had severe transfusion-dependent, presumably homozygous elliptocytosis and both parents had asymptomatic elliptocytosis. Red cell membranes of all 3 sibs showed an excess of spectrin dimers over tetramers in spectrin extracts. Both parents showed an intermediate increase in spectrin dimers.

In 7 black patients (from 5 unrelated families) with mild HE, Lecomte et al. (1985) found an abnormal thermal sensitivity and an important defect of spectrin dimer self-association. An excess of spectrin dimer and deficient dimer-to-tetramer conversion were demonstrated. Peptide patterns of crude spectrin showed a marked decrease in the 80-kD peptide (previously identified as the dimer-dimer interaction domain of the alpha chain) and a concomitant appearance of a novel 65-kD peptide. Anti-alpha-spectrin antibodies showed that the latter peptide was derived from the alpha chain. The patients were 3 unrelated adults, 2 children with hemolytic anemia, and the father of each child.

Lawler et al. (1984, 1985) described a molecular defect in the alpha subunit of spectrin in a subset of patients with hereditary elliptocytosis; the self-association of alpha-beta heterodimers to form tetramers was defective.

Abnormality of alpha spectrin was reported by Ravindranath and Johnson (1985) in a case of congenital hemolytic anemia.

Lambert and Zail (1987) also found a variant of the alpha subunit. Two brothers with the poikilocytic variant of hereditary elliptocytosis were found to have a defect in spectrin dimer association and a decreased spectrin/band 3 ratio. The major abnormal tryptic peptides derived from the alpha-I domain had lower molecular weights and more basic isoelectric points than hitherto described. The propositus of Lambert and Zail (1987) was a black South African miner.

In a 6-week-old black infant, Garbarz et al. (1986) found hemolytic anemia with red cell fragmentation, poikilocytosis, and elliptocytosis. Both parents and a brother of the propositus had compensated mild hereditary elliptocytosis. Studies indicated that the proband was homozygous for an alpha-I/65 spectrin variant whereas both parents were heterozygous.

In a family with hereditary elliptocytosis, Lane et al. (1987) found that alpha-spectrin subunits migrated anomalously in SDS-PAGE. The quantity of the alpha-spectrin mutant, expressed as a percentage of the total alpha spectrin, varied from 9.9 to 45.2% among 6 affected persons. Other findings suggested that this new alpha-spectrin mutant is responsible for decreased spectrin dimer-dimer association and for red cell instability. The propositus, a 23-month-old boy, exhibited anemia, hyperbilirubinemia requiring phototherapy, and striking red cell poikilocytosis at birth. His only sib, a 4-year-old who had hyperbilirubinemia at birth, exhibited elliptocytosis without poikilocytosis at the time of study. The mother, 2 of her sibs, and the maternal grandfather had elliptocytosis.

Mapping

Morton (1956) defined the existence of Rh-linked (611804) and Rh-unlinked forms of elliptocytosis and emphasized the usefulness of linkage studies in demonstration of genetic heterogeneity.

Keats (1979) suggested that a second elliptocytosis locus unlinked to Rh is on chromosome 1. She found a lod score of 1.97 for theta of 0.0 for linkage with Duffy.

Molecular Genetics

By in situ hybridization, the SPTA1 gene was mapped to 1q22-1q25 (Huebner et al., 1985) in the region proposed by Keats (1979) for a non-Rh-linked form of elliptocytosis. In patients with elliptocytosis, Marchesi et al. (1987) identified heterozygous mutations in the SPTA1 gene (182860.0001-182860.0002). This is one of the first examples of positive results from the 'candidate gene' approach to elucidating etiopathogenesis.

History

From analysis of the data by a maximum likelihood method, Rao et al. (1979) concluded that there is 'nonsignificant evidence of linkage' of an Rh-unlinked form of elliptocytosis to chromosome 1 (lod score, 2.08).