In 9 individuals from 5 unrelated families with hereditary elliptocytosis (EL2; 130600) or hereditary pyropoikilocytosis (HPP; 266140), including one of the original HPP probands reported by Zarkowsky et al. (1975), Gallagher et al. (1992) found the alpha-I/46-50a peptide after limited tryptic digestion of spectrin. Further studies identified a point mutation causing the replacement of a highly conserved leucine residue by proline at position 207 in the alpha-spectrin chain, a site 51 residues to the amino-terminal side of the abnormal proteolytic cleavage site. Dalla Venezia et al. (1993) found the leu207-to-pro mutation in a Moroccan family in both homozygous and heterozygous states. The mutated allele carried, in cis, the common alpha-V/41 polymorphism, which is associated with a low expression level. Dalla Venezia et al. (1993) suggested that the cis combination of an HE mutation and the alpha-V/41 polymorphism accounts for the low expression of the abnormal allele in the heterozygous state.
In the original family of Zarkowsky et al. (1975), the L207P mutation was in compound heterozygous state with an SPTA1 allele associated with a defect in alpha-spectrin production. By analysis of reticulocyte alpha-spectrin cDNA from 1 of the original HPP patients, Costa et al. (2005) identified a G-to-A transition (182860.0024) at position +5 of the donor splice site of intron 22 of the SPTA1 gene, resulting in insertion of intronic fragments and an in-frame premature termination codon. Following gene transfer of the IVS22+5 mutation into tissue culture cells, there was complete absence of normally spliced SPTA1 gene transcript.
