Hereditary Spherocytosis with Spectrin Deficiency Related to Null Mutations of the β-Spectrin Gene

ABSTRACT: Spectrin deficiency is the most common deficiency found in HS. It is heterogeneous in terms of clinical expression, inheritance (dominant or recessive) and underlying genetic defects (related to α- or β-spectrin gene defects or secondary to ankyrin gene defects). We studied a sampling of French dominant HS families, selected after linkage analyses, and found the presence of mutations resulting in the silencing of the mutant β-spectrin allele. In three HS families, one haploid set of β-spectrin mRNA was undectectable. In two families, a deletion of 8 bases (leading to a frameshift and a premature stop codon) and a nonsense mutation were identified, respectively. In the third HS family, we were unable to characterize a relevant mutation but the loss of heterozygosity at the cDNA level suggested the presence of a null mutation of the β-spectrin allele. Sequencing of the β-spectrin gene has also uncovered several new polymorphisms in the coding region of the β-spectrin gene which will be very useful for detecting loss of heterozygosity at the cDNA level and designating the β-spectrin gene as the culprit one.