A 5' splice region G → C mutation in exon 3 of the human β-spectrin gene leads to decreased levels of β-spectrin mRNA 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 β-spectrin gene (SPTB) showed that HS co-segregated with alleles of these microsatellite markers and the linkage between the marker and HS was statistically significant. The presence of a β-spectrin protein polymorphism (β-spectrin Vay; A1880V) in trans of the HS allele was not itself deleterious, but allowed the detection of decreased membrane expression of the spherocytic β-spectrin allele in two HS-affected subjects. Direct sequencing of the coding exons of the β-spectrin gene in one affected subject showed the presence of a G → C transversion at the terminal nucleotide of exon 3, which did not change the leucine codon 100 (CTG → CTC). The presence of the mutation was confirmed by restriction enzyme digestion at the DNA level in all affected SH members of the family. The G → C mutation severely reduced the utilization of the 5' splice site and resulted in aberrant mRNA splicing with intron 3 retention.