Dr. Richard Gatti's research focuses on the molecular genetics of ataxia-telangiectasia (A-T). A-T is a progressive neurological disorder of childhood associated with increased cancer risk, immunodeficiency, radiosensitivity and cell cycle defects.
In 1988, Gatti and associates localized the gene for A-T to chromosome 11q22-23 by linkage analyses. To fine map the region, they formed an international consortium of over 200 families and localized the gene to within 500 kb by classical linkage analysis. In 1995, the ATM (A-T mutated) gene was cloned and found to be a serine-threonine kinase that plays a hierarchical role in cell signaling and DNA repair.
Gatti and his colleagues are presently identifying and characterizing how ATM mutations cause disease in A-T patients. For diagnostic services, they perform immunoblotting and assay radiosensitivity; both require that a cell line be established on each incoming blood sample. This provides a renewal sample for many additional lab studies.
Other projects in the lab include analyzing DNA repair and cell signaling proteins on a panel of 40 radiosensitive cell lines from non-AT patients; testing the function of ATM DNA variants in a mutagenesis assay that involves making stable transfections; constructing minigenes to detect aberrant splicing within the many exons in the ATM gene; producing recombinant ATM in a vaccinia expression system for structural studies of ATM; and aminoglycoside-induced expression of ATM protein as a potential therapeutic approach. This therapy might be useful for about 15 percent of A-T patients worldwide.
Gatti's long-term goals are gene-based therapy and improved diagnostic testing for patients and carriers who are at an increased risk of cancer.
Selected Cancer-Related Publications:
Ambrose M, Goldstine JV, Gatti RA. Intrinsic mitochondrial dysfunction in ATM-deficient lymphoblastoid cells. Hum Mol Genet. 2007; 16:1-11.
Du L, Pollard J, Gatti RA. Correction of prototypic ATM splicing mutation and aberrant ATM function with antisense morpholino oligonucleotides. PNAS. 2007; 104:6007-6012.
Cavalieri S, Funaro A, Porcedda P, Turinetto V, Migone N, Gatti RA, Brusco A. ATM mutations in Italian families with ataxia-telangiectasia include two distinct large genomic deletiions. Hum Mutation. 2006; 27:1061-71.
Langolz B, Bernstein JL, Bernstein L, Olsen JH, Borresen-Dale AL, Rosenstein BS, Gatti RA, Concannon P. On the proposed association of the ATM variants 5557G>A and IVS38-8T>C and bilateral breast cancer. Int J Cancer. 2006; 119:724-5.
Pashankar F, Singhal V, Akabogu I, Gatti RA, Goldman FD. Intact T cell responses in ataxia telangiectasia. Clin Immunol. 2006; 120:158-162.