A 5'-SPLICE REGION G-]C MUTATION IN EXON-3 OF THE HUMAN BETA-SPECTRINGENE LEADS TO DECREASED LEVELS OF BETA-SPECTRIN MESSENGER-RNA AND IS RESPONSIBLE FOR DOMINANT HEREDITARY SPHEROCYTOSIS (SPECTRIN GUEMENE-PENFAO)

We studied a family with autosomal dominant hereditary spherocytosis ( HS) associated with a mild spectrin deficiency. Linkage analysis using two microsatellite markers (D14S63 and (D14S271) very close to the be ta-spectrin gene (SPTB) showed that HS co-segregated with alleles of t hese microsatellite markers and the linkage between the marker and HS was statistically significant. The presence of a beta-spectrin protein polymorphism (beta-spectrin Vay; A1880V) in trans of the HS allele wa s not itself deleterious, but allowed the detection of decreased membr ane expression of the spherocytic beta-spectrin allele in two HS-affec ted subjects. Direct sequencing of the coding exons of the beta-spectr in gene in one affected subject showed the presence of a G --> C trans version at the terminal nucleotide of exon 3, which did nut change the leucine codon 100 (CTG --> CTC). The presence of the mutation was con firmed by restriction enzyme digestion at the DNA level in all affecte d SH members of the family. The G --> C mutation severely reduced the utilization of the 5' splice site and resulted in aberrant mRNA splici ng with intron 3 retention.