HEREDITARY SPHEROCYTOSIS WITH SPECTRIN DEFICIENCY RELATED TO NULL MUTATIONS OF THE BETA-SPECTRIN GENE

Spectrin deficiency is the most common deficiency found in HS. It is h eterogeneous in terms of clinical expression, inheritance (dominant or recessive) and underlying genetic defects (related to alpha- or beta- spectrin gene defects or secondary to ankyrin gene defects). We studie d a sampling of French dominant HS families, selected after linkage an alyses, and found the presence of mutations resulting in the silencing of the mutant beta-spectrin allele, In three HS families, one haploid set of beta-spectrin mRNA was undectectable, In two families, a delet ion of 8 bases (leading to a frameshift and a premature stop codon) an d a nonsense mutation were identified, respectively. In the third HS f amily, 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 beta-spectrin allele, Sequencing of the beta-spectrin gene has also uncovered several new polymorphisms in the coding region of the beta-spectrin gene which will be very useful for detecting los s of heterozygosity at the cDNA level and designating the beta-spectri n gene as the culprit one. (C) 1998 Academic Press.