Germline, loss-of-function mutations in the human retinoblastoma gene confer hereditary susceptibility to a variety of cancers, most notably retinoblastoma. Since the last competitive review, research funded by this grant has been successful in cloning this tumor suppressor gene. The isolation of this gene has allowed the applicants to pursue a number of investigations of the gene, including its relationship to retinoblastoma and other human cancers and its value in the genetic diagnosis of retinoblastoma. In this competing continuation application, the applicants propose to continue their studies of this locus. In particular, the applicants and others have documented the existence of patients who are mosaic for mutations of the retinoblastoma gene; they now wish to ascertain the frequency of such mosaicism. Another study involves a more precise measurement of the percentage of new germline mutations that occur on the paternally derived copy of the retinoblastoma gene, as opposed to the maternally derived copy. The applicants will explore the incidence of and significance of methylation of the 5' end of the retinoblastoma gene. Experiments aimed at identifying the factors important in the regulation of transcription of the retinoblastoma gene will be carried out. Finally, the applicants propose to demarcate functional domains of the protein encoded by the retinoblastoma gene by searching for regions of the primary structure that are conserved through evolution. Many of these studies have direct relevance to the clinical care of patients with retinoblastoma and their families.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY005321-10
Application #
3260354
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1982-09-30
Project End
1995-11-30
Budget Start
1991-12-06
Budget End
1992-11-30
Support Year
10
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Massachusetts Eye and Ear Infirmary
Department
Type
DUNS #
073825945
City
Boston
State
MA
Country
United States
Zip Code
02114
Wiggs, J L; Dryja, T P (1988) Predicting the risk of hereditary retinoblastoma. Am J Ophthalmol 106:346-51
Wiggs, J; Nordenskjold, M; Yandell, D et al. (1988) Prediction of the risk of hereditary retinoblastoma, using DNA polymorphisms within the retinoblastoma gene. N Engl J Med 318:151-7