MOLECULAR GENETICS OF FANCONI ANEMIA

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.