IDENTICAL MUTATION IN 55-PERCENT OF THE ATM ALLELES IN 11 NORWEGIAN AT FAMILIES - EVIDENCE FOR A FOUNDER EFFECT

The ATM gene is responsible for the autosomal recessive disorder Ataxi a-Telangiectasia (AT). Many different mutations, located all across th e gene, have been reported with a predominance of truncating mutations . By using PTT (protein truncation test) a mutation was found in one N orwegian AT family. Sequencing revealed that the mutation affected nuc leotides 3245-3247, codon 1082, and changed the sequence from ATC to T GAT, inducing a stop codon downstream at codon 1095 and leading to ear ly truncation of the ATM protein. Perpendicular DGGE (denaturing gradi ent gel electrophoresis) was used to screen 10 additional families for this mutation. The 3245 delATC insTGAT mutation was found in 12 of 22 proband alleles: five patients were homozygotes and two heterozygotes . Haplotype analyses were performed using eight microsatellite markers , within and flanking the ATM gene. All carriers of the mutation descr ibed were found to have a common haplotype of the five closest CA-repe at microsatellite markers. Genealogical investigations of the families identified a common ancestor for three of the families. The common an cestor was a woman born in 1684 in the area from which these families originate. The prevalence of this mutation in Norwegian patients now a llows a major subset of AT heterozygotes to be identified, both in the general population and in breast cancer patients, so that their cance r risk can be evaluated.