Independent mutational events are rare in the ATM gene: Haplotype prescreening enhances mutation detection rate

Abstract

Mutations in the ATM gene are responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T). Many different mutations have been identified using various techniques, with detection efficiencies ranging from 57 to 85%. In this study, we employed short tandem repeat (STR) haplotypes to enhance mutation identification in 55 unrelated A-T families of Iberian origin (20 Spanish, 17 Brazilian, and 18 Hispanic-American); we were able to identify 95% of the expected mutations. Allelic sizes were standardized based on a reference sample (CEPH 1347-2). Subsequent mutation screening was performed by PTT, SSCP, and DHPLC, and abnormal regions were sequenced. Many STR haplotypes were found within each population and six haplotypes were observed across several of these populations. Single nucleotide polymorphism (SNP) haplotypes further suggested that most of these common mutations are ancestrally related, and not hot spots. However, two mutations (8977C>T and 8264_8268delATAAG) may indeed be recurring mutational events. Common haplotypes were present in 13 of 20 Spanish A-T families (65%), in 11 of 17 Brazilian A-T families (65%), and, in contrast, in only eight of 18 Hispanic-American families (44%). Three mutations were identified that would be missed by conventional screening strategies. In all, 62 different mutations (28 not previously reported) were identified and their associated haplotypes defined, thereby establishing a new database for Iberian A-T families, and extending the spectrum of worldwide ATM mutations.

Five haplotypes account for fifty‐five percent of ATM mutations in Brazilian patients with ataxia telangiectasia: Seven new mutations

“…This suggests that the C-terminus end of the protein may also participate in the stabilization of the ATM protein [Becker-Catania et al, 2000]. Five mutations identified in the studied group had been previously observed in different European populations: Spain (640delT, 5644C > T, 8264delATAAG), Germany (3802delG), and Italy (7517delGAGA) (Gilad et al, 1996;Mitui et al, 2003]. These data corroborate the genetic findings of other authors that a variety of European backgrounds contribute to Brazilian lineages [Salzano and Freire-Maia, 1967;Raskin et al, 1999;Carvalho-Silva et al, 2001].…”

“…It was not possible to precisely define the break points. This mutation was previously identified in Costa Rican AT patients and also in patients of Iberian origins [Telatar et al, 1996;Mitui et al, 2003]. …”

“…Primers were designed to flank each STR and used for PCR amplification by g 33 P-ATP end-radiolabeled fragments Mitui et al, 2003]. Alleles were standardized using a control DNA, CEPH 1347-2.…”

ATM mutations in Italian families with ataxia telangiectasia include two distinct large genomic deletions

“…Finally, AT7TO carries a novel haplovariant [A 3 ] characterized by a variation of three 2-bp repeats at the D11S1819 marker. (2) The second recurrent haplotype (Haplotype L) was found in AT18TO; it has been previously described in association with the c.7517_7520delGAGA mutation in A-T patients from France and Brazil Mitui et al, 2003). (3) In AT13TO one of the two haplotypes (Haplotype H) has been previously associated with the c.2250 G>A mutation .…”

p53 centrosomal localization diagnoses ataxia-telangiectasia homozygotes and heterozygotes

“…The ATM gene contains 66 exons spanning approximately 160 Kb of genomic DNA (8), and a large variety (>600) of mutations occurs across the fulllength transcript without hotspots. In addition, like other large genes, ATM possesses many polymorphisms that must be distinguished from mutations (9,10).…”