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- Title
p53 centrosomal localizatio n diagnoses ataxia-telangiectasia homozygotes and heterozygotes.
- Authors
Prodosmo, Andrea; De Amicis, Andrea; Nisticò, Cecilia; Gabriele, Mario; Rocco, Giuliana Di; Monteonofrio, Laura; Piane, Maria; Cundari, Enrico; Chessa, Luciana; Soddu, Silvia
- Abstract
Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder characterized by radiosensi-tivity, genomic instability, and predisposition to cancer. A-T is caused by biallelic mutations in the ataxia-te-langiectasia mutated (ATM) gene, but heterozygous carriers, though apparently healthy, are believed to be at increased risk for cancer and more sensitive to ionizing radiation than the general population. Despite prog-ress in functional and sequencing-based assays, no straightforward, rapid, and inexpensive test is available for the identification of A-T homozygotes and heterozygotes, which is essential for diagnosis, genetic counseling, and carrier prediction. The oncosuppressor p53 prevents genomic instability and centrosomal amplification. During mitosis, p53 localizes at the centrosome in an ATM-dependent manner. We capitalized on the latter finding and established a simple, fast, minimally invasive, reliable, and inexpensive test to determine mutant ATM zygosity. The percentage of mitotic lymphoblasts or PBMCs bearing p53 centrosomal localization clearly discriminated among healthy donors (>75%), A-T heterozygotes (40%-56%), and A-T homozygotes (<30%). The test is specific for A-T, independent of the type of ATM mutations, and recognized tumor-associated ATM polymorphisms. In a preliminary study, our test confirmed that ATM is a breast cancer susceptibility gene. These data open the possibility of cost-effective, early diagnosis of A-T homozygotes and large-scale screenings for heterozygotes.
- Subjects
ATAXIA telangiectasia; P53 antioncogene; CENTROSOMES; GENETIC carriers; MITOSIS; COST effectiveness; GENOMICS
- Publication
Journal of Clinical Investigation, 2013, Vol 123, Issue 3, p1335
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI67289