Fanconi anemia is an autosomal recessive disease which shows developmental delay, skeletal abnormalities, pancytopenia of marrow cells, altered skin pigmentation and increased risk of leukemia. Fanconi anemia therefore presents alterations in growth and development with anemia, and is an autosomal recessive disease with an increased risk of cancer. There are four complementation groups, indicating the involvement of defects in multiple genes in the disease. This Program Project will use a molecular genetic approach to define the genetic elements causing Fanconi anemia (the gene responsible for Fanconi anemia complementation Group C has been identified) (II). The concept of this project is to bring a multidisciplinary approach to the study of the molecular defects, diagnosis, and definition of the causes of Fanconi anemia at the molecular and cellular level. The clinical disciplines represented by the Investigators include internal medicine, pediatrics, medical genetics, hematology and oncology. The proposed project will have three investigative components and three core components: Project 1 will use cDNA expression vectors to identify Fanconi anemia genes by complementation and to define the action of the products of these genes in DNA repair. Project 2 will undertake positional cloning to identify Fanconi anemia genes and will characterize Fanconi anemia genes defects by mutational analysis. Project 3 will use marrow cell cultures to define the function of Fanconi anemia genes in hematopoiesis. The Cytogenetics Core will apply testing of chromosome-breakage in new Fanconi anemia cell line candidates and in testing the function of candidate Fanconi anemia genes. The Fanconi Anemia Cell Repository will identify Fanconi anemia cell lines for complementation testing and establish permanent cell lines for Investigators.
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