ATM gene founder haplotypes and associated mutations in Polish families with ataxia-telangiectasia.
Ataxia-telangiectasia (A-T) is an early onset autosomal recessive ataxia associated with characteristic chromosomal aberrations, cell cycle checkpoint defects, cancer susceptibility, and sensitivity to ionizing radiation. We utilized the protein truncation test (PTT), and single strand conformation polymorphism (SSCP) on cDNA, as well as denaturing high performance liquid chromatography (dHPLC) on genomic DNA (gDNA) to screen for mutations in 24 Polish A-T families. Twenty-six distinct Short Tandem Repeat (STR) haplotypes were identified. Three founder mutations accounted for 58% of the alleles. Three-quarters of the families had at least one recurring (shared) mutation, which was somewhat surprising given the low frequency of consanguinity in Poland. STR haplotyping greatly improved the efficiency of mutation detection. We identified 44 of the expected 48 mutations (92%): sixty-nine percent were nonsense mutations, 23% caused aberrant splicing, and 5% were missense mutations. Four mutations have not been previously described. Two of the Polish mutations have been observed previously in Amish and Mennonite A-T patients; this is compatible with historical records. Shared mutations shared the same Single Nucleotide Polymorphism (SNP) and STR haplotypes, indicating common ancestries. The Mennonite mutation, 5932 G>T, is common in Russian A-T families, and the STR haplovariants are the same in both Poland and Russia. Attempts to correlate phenotypes with genotypes were inconclusive due to the limited numbers of patients with identical mutations.
Mitui
M
M
Department of Pathology and Laboratory Medicine, The David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, CA 90095-1732, USA.
Bernatowska
E
E
Pietrucha
B
B
Piotrowska-Jastrzebska
J
J
Eng
L
L
Nahas
S
S
Teraoka
S
S
Sholty
G
G
Purayidom
A
A
Concannon
P
P
Gatti
R A
RA
D000293:Adolescent; D001260:Ataxia Telangiectasia / Q000453:epidemiology / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D004268:DNA-Binding Proteins / Q000235:genetics*; D005190:Family; D005260:Female; D018703:Founder Effect; D006239:Haplotypes / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D011044:Poland / Q000453:epidemiology; D018807:Polymorphism, Single-Stranded Conformational; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases