A well established and senior investigator in the field of AT has proposed this work to improve the diagnosis and treatment of AT. The proposal aims to understand the relationship between specific mutations and clinical symptoms. Because as many as 1% of the general population may carry a defective ATM (A-T mutated) gene, and these individuals may compromise perhaps 5% of all cancer patients, it is hoped that these studies will also offer better diagnosis for AT-carriers. The ATM gene is large, with 66 small exons, thereby presenting a challenging technical problem for mutation screening. At UCLA, Dr. Gatti has a unique repository of cells, mRNAs, and DNAs from greater than 200 A-T patients and their families. This resource allowed him to play a major role in the positional cloning that led to the isolation of the ATM gene in 1995. Since then greater than 200 mutations have been defined; more than half of these have come from his laboratory. Almost all of these mutations have been detected by screening mRNA/cDNA, using a protein truncation test and conformation sensitive gel electrophoresis (CSGE). Dr. Gatti will complete the task of defining cDNA defects and their corresponding genomic (gDNA) mutations on the remaining cDNAs and their screen DNA on 100 additional patients from whom cDNA is not available. Dr. Gatti will use restriction endonuclease finger printing, chemical cleavage, and semi-automated single strand conformational polymorphism screening methods. He will also participate in testing the efficiency of """"""""smart chips"""""""" and other newly-introduced screening techniques in order to minimize the amount of actual sequencing necessary to define each mutation. Since most patients are compound heterozygotes, his resources should allow the characterization of 400 mutations. Dr. Gatti will also determine the affected haplotypes for each patient and, whenever possible, within each family. He will then compare the type and site of each mutation with the clinical symptoms of patients from multiple-affected families and ethnic groups with founder effect mutations. Families with variant phenotypes will be studied. Dr. Gatti anticipates that his research project will ultimately help to define the single common biological mechanism that underlies this complex syndrome. Based on this understanding, he then hopes to design a rational approach to an effective therapy of the affected children.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS035322-04
Application #
6343866
Study Section
Special Emphasis Panel (ZRG1-NLS-3 (02))
Program Officer
Spinella, Giovanna M
Project Start
1998-01-01
Project End
2001-12-31
Budget Start
2001-01-01
Budget End
2001-12-31
Support Year
4
Fiscal Year
2001
Total Cost
$304,028
Indirect Cost
Name
University of California Los Angeles
Department
Pathology
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Gatti, Richard A; Perlman, Susan (2009) A proposed bailout for A-T patients? Eur J Neurol 16:653-5
Mitui, M; Nahas, S A; Du, L T et al. (2009) Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: mutations with increased cancer risk. Hum Mutat 30:12-21
Hu, Hailiang; Gatti, Richard A (2008) New approaches to treatment of primary immunodeficiencies: fixing mutations with chemicals. Curr Opin Allergy Clin Immunol 8:540-6
Cavalieri, Simona; Funaro, Ada; Pappi, Patrizia et al. (2008) Large genomic mutations within the ATM gene detected by MLPA, including a duplication of 41 kb from exon 4 to 20. Ann Hum Genet 72:10-8
Ambrose, Mark; Goldstine, Jimena V; Gatti, Richard A (2007) Intrinsic mitochondrial dysfunction in ATM-deficient lymphoblastoid cells. Hum Mol Genet 16:2154-64
Landmark, H; Nahas, S A; Aaroe, J et al. (2007) Transcriptional response to ionizing radiation in human radiation sensitive cell lines. Radiother Oncol 83:256-60
Lavin, Martin F; Gueven, Nuri; Bottle, Stephen et al. (2007) Current and potential therapeutic strategies for the treatment of ataxia-telangiectasia. Br Med Bull 81-82:129-47
Du, Liutao; Pollard, Julianne M; Gatti, Richard A (2007) Correction of prototypic ATM splicing mutations and aberrant ATM function with antisense morpholino oligonucleotides. Proc Natl Acad Sci U S A 104:6007-12
Cavalieri, Simona; Funaro, Ada; Porcedda, Paola et al. (2006) ATM mutations in Italian families with ataxia telangiectasia include two distinct large genomic deletions. Hum Mutat 27:1061
Babaei, Mahnoush; Mitui, Midori; Olson, Eric R et al. (2005) ATM haplotypes and associated mutations in Iranian patients with ataxia-telangiectasia: recurring homozygosity without a founder haplotype. Hum Genet 117:101-6

Showing the most recent 10 out of 26 publications