(ATT) TRINUCLEOTIDE REPEATS IN THE ANTITHROMBIN GENE AND THEIR USE INDETERMINING THE ORIGIN OF REPEATED MUTATIONS

Two (ATT) trinucleotide repeat polymorphisms have been identified in t he tails of Alu repeat elements in intron 5 of the antithrombin gene. The frequency and distribution of allele sizes for the Alu 5 and Alu 8 tail polymorphisms have been defined in a sample Caucasian population , The Alu 5 polymor phism has two alleles while that of Alu 8 has 10 a lleles with a heterozygosity of 0.83. These polymorphisms have been us ed in combination with four previously described polymorphisms within the antithrombin gene to construct antithrombin gene haplotypes in the sample Caucasian population. Twenty-two different haplotypes were obs erved, with the Alu 8 polymorphism being particularly useful in subdiv iding the core haplotype based on the previously identified polymorphi sms. The hap lotype data were used to investigate the origin of repeat mutations within the antithrombin locus. We compared the haplotypes a ssociated the mutant antithrombin genes in five families with the muta tion 2159C-->T (L99F) and five families with the mutation 5381C-->T (R 129Stop), The mutation 2759C-->T (L99F), which occurs within a non-CpG dinucleotide, was carried on a gene associated with an identical hapl otype in each of the five families. The mutation 5381C-->T (R129Stop), a single base substitution within a CpG dinucleotide, was associated with at least two different haplotypes. The findings suggest a founder effect in the five families sharing the 2759C-->T (L99F) and at least two independent origins for the CpG dinucleotide mutation 5381C-->T ( R129Stop). (C) 1994 Wiley-Liss, Inc.