Dr. Richard A. Gatti
UCLA School of Medicine
Department of Pathology
Los Angeles, CA 90095-1732
Phone: 310-825-7618
Fax: 310-825-7618
Email: rgatti@pathology.medsch.ucla.edu
Projects are approved by an IRB located at: UCLA School of Medicine, Department of Pathology.
The approving IRB operates under a Multiple Project Assurance (MPA) recognized by DOE or by the Department of Health and Human Services (HHS).
MPA number of the IRB: M-1127
Number of Human Subjects Projects reported: 1
Project Identifier: UCLA-87-ER-60548
Project Title:
Human Gene for Radiation Hypersensitivity
Principal Investigator:
Dr. Richard A. Gatti
Principal Investigator's Institution: UCLA School of Medicine
Project started in: 1987
Project Funding Information:
Project received funding in Fiscal Year 1998.
Project used human subjects in Fiscal Year 1998.
Funding Sources:
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: September 30, 1997
IRB Approval Number: 93-07-260-04
Number of Human Subjects who participated in this project/protocol during
06/17/97 - 06/16/98: 10
Type of Human Subjects Involvement:
Human Gene for Radiation Hypersensitivity ER-60548 Gatti
Objectives. In 1981, our laboratory set out to isolate the gene or genes for ataxia-telangiectasia, a gene that when defective causes a fascinating array of biological aberrations as well as a progressive and uniformly fatal neurological disorder of children. We argued at the time, against conventional wisdom, that the complexity of the biochemistry, neurobiology, radiobiology and immunology were unlikely to be unraveled before a gene could be localized in the human genome by linkage analysis and isolated by molecular cloning techniques. In June 1995, this prediction was realized, entirely by positional cloning. The gene was mapped to within the 500 - kb 2-lod support interval that we were able to define by linkage analyses of a consortium of almost 200 families, collected from primarily nine countries over the past six years. This is perhaps the best example to date of the power and accuracy of "positional cloning" for isolating disease genes. A Markov chain-based Monte Carlo analysis program that takes ~ 125 hours to calculate lod scores on these families (using a mainframe IBM computer) was developed especially for this project and is now available worldwide for other linkage analysis projects. Three generations of graduate students and fellows in biomathematics and molecular biology were trained during this time.
The long term objectives of the proposed project are to capitalize on the recent isolation of the A-T gene by developing diagnostic tests that will identify persons at risk for radiation sensitivity and cancer, both in the workplace and in the general environment. We also hope to develop new therapeutic approaches for: 1) A-T, 2) cancer, and 3) protection from radiation damage. Before we can hope to achieve any therapeutic successes, however, we must learn a great deal more about the function and sites of action of the newly-cloned gene. We plan to do this by first analyzing the mutations of over 200 families and correlating this information with the clinical variations observed within each family and within various ethnic subsets. Hopefully, this information will be in place when the functional domains, tertiary structure, and biochemical characteristics of the molecule are elucidated.
Methodology: Blood drawing. Normal risks associated with blood drawing. Benefits include those to mankind, not to individual donors. Most donors are members of families with patients affected with ataxia-telangiectasia (AT). Age range of unaffected blood donors is from about ten years to over 80. Minors are asked to volunteer for the study by their parents and not by the investigator. Age range of donors affected with AT is typically between 2 and 10 years old. The amount of blood drawn will vary with body size. A very small child will only have 10-15ml drawn at one time. The PI is a pediatrician by training and is well acquainted and sensitive to these limitations. The PI draws almost all blood specimens himself. Approximately 50 ml is drawn from adults, approximately once every several years.
Ionizing radiation to subjects:none
Involvement of human subjects. Because the study is closing in March 1999, we are not longer recruiting new families. We are completing our genetic analyses of existing DNAs and RNAs. All of these were obtained under approved HSPC protocols and with approved consent forms.
Risks: We have tried, whenever possible, to obtain blood samples whenever blood was being drawn for other reasons.
Confidentiality. We have found that the best identification for biological samples in the laboratory is the donor's full name printed clearly on the specimen container. In addition, an laboratory identification is provided. Once in the laboratory, the samples are then referred to in lab books and reports by the lab identification. However, some form of the donors initials accompany the specimens in some laboratory records so as to avoid sample mix-ups between relatives with very similar first and last names. When data are published all such identifications are removed in favor of an internationally agreed upon nomenclature in our field. However, in large family pedigrees it is not impossible that a family member might be able to identify certain key individuals, such as the parents or grandparents. If they are indicated to be A-T carrier, such information might be obtainable from a publication. We have attempted to include "dummy" or false information in such pedigrees but this leads to scientific confusion in other laboratories who wish to check or extend our data analyses. It also leads to lab errors in analyzing family data. Also, it does successfully mask key members of the pedigree. Lastly, the data are never destroyed since such family studies are never really terminated: they are ongoing and might be reactivated at any time in the future as better technology comes along to resolve ongoing questions.