Occurrence of the αI 22 Arg→His (CGT→CAT) spectrin mutation in Tunisia: potential association with severe elliptopoikilocytosis

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Abstract
Summary A category of spectrin αI domain variants are manifested by the increase of the αI 74 kDa fragment at the expense of the parent 80 kDa fragment following partial tryptic digestion. We describe a particular case of αI/74 abnormality in a Tunisian family. The propositus was severely ill and had an elliptopoikilocytosis. To the contrary, his father, who carried the same αI/74 variant, displayed no clinical signs and a few elliptocytes. The increase of the αI 74 kDa fragment was more pronounced in the propositus than in his father. Unexpectedly, the spectrin content was reduced to similar (and limited) extents in both of them, and the father displayed nearly as pronounced an increase of the spectrin dimer percentage as the propositus following low ionic strength extraction. In vitro spectrin dimer reconstitution experiments indicated that the primary mutation was located in the α‐chain itself (not in the β‐chain as is the case in some αI/74 mutants). Following polymerase chain reaction (PCR) amplification, cloning and sequencing of exon 2 of spectrin α‐gene in the father, we found the G→A substitution at position 2 of codon 22 (CGT→CAT; Arg→His). This mutation has been recently discovered in a family of French descent. Dot blot hybridization confirmed that the substitution was transmitted with the αI/74 abnormality. As previously shown, the enhancement of its expression level in the propositus, with respect to the father, was accounted for by the presence of a factor carried by the α‐spectrin allele in trans and transmitted by the mother.