ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer.

  • Stankovic T
  • Kidd A
  • Sutcliffe A
 et al. 
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We report the spectrum of 59 ATM mutations observed in ataxia-telangiectasia (A-T) patients in the British Isles. Of 51 ATM mutations identified in families native to the British Isles, 11 were founder mutations, and 2 of these 11 conferred a milder clinical phenotype with respect to both cerebellar degeneration and cellular features. We report, in two A-T families, an ATM mutation (7271T-->G) that may be associated with an increased risk of breast cancer in both homozygotes and heterozygotes (relative risk 12.7; P=. 0025), although there is a less severe A-T phenotype in terms of the degree of cerebellar degeneration. This mutation (7271T-->G) also allows expression of full-length ATM protein at a level comparable with that in unaffected individuals. In addition, we have studied 18 A-T patients, in 15 families, who developed leukemia, lymphoma, preleukemic T-cell proliferation, or Hodgkin lymphoma, mostly in childhood. A wide variety of ATM mutation types, including missense mutations and in-frame deletions, were seen in these patients. We also show that 25% of all A-T patients carried in-frame deletions or missense mutations, many of which were also associated with expression of mutant ATM protein.

Author-supplied keywords

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Ataxia Telangiectasia
  • Ataxia Telangiectasia Mutated Proteins
  • Ataxia Telangiectasia: genetics
  • Breast Neoplasms
  • Breast Neoplasms: epidemiology
  • Breast Neoplasms: genetics
  • Cell Cycle Proteins
  • Chromosome Mapping
  • DNA-Binding Proteins
  • Female
  • Genetic Markers
  • Great Britain
  • Haplotypes
  • Heterozygote Detection
  • Homozygote
  • Humans
  • Leucine Zippers
  • Leukemia
  • Leukemia: epidemiology
  • Leukemia: genetics
  • Lymphoma
  • Lymphoma: epidemiology
  • Lymphoma: genetics
  • Male
  • Middle Aged
  • Mutation
  • Pedigree
  • Phenotype
  • Point Mutation
  • Protein-Serine-Threonine Kinases
  • Proteins
  • Proteins: genetics
  • Risk Factors
  • Sequence Deletion
  • Tumor Suppressor Proteins

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  • T Stankovic

  • A M Kidd

  • A Sutcliffe

  • G M McGuire

  • P Robinson

  • P Weber

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