DEVELOPMENTAL EXPRESSION OF THE FAC GENE CORRELATES WITH CONGENITAL-DEFECTS IN FANCONI-ANEMIA PATIENTS

Fanconi anemia (FA) is a genetically heterogeneous, autosomal recessiv e disorder characterized by a variety of congenital and skeletal malfo rmations, progressive pancytopaenia and predisposition to malignancies . While the basic defect in this disease is not known, the cloning of the gene defective in FA group C patients (FAC) allows analysis of its expression pattern, which may provide clues about the functional prop erties of the protein. This paper describes the distribution of Fac tr anscripts during murine development (8-19.5 days p.c.), using RNA in s itu hybridization. Fac is initially expressed (8-10 days p.c.) in the mesenchyme and its derivatives with osteogenic potential. The transcri pt is also apparent at later stages of bone development (13-19.5 days p.c.), localized to cells of the inner perichondrium, periosteum and z one of endochondral ossification, In the latter, Fac transcripts are s een in cells from both osteogenic and hematopoietic lineages. Fac mRNA is also seen in intramembranous cranial and facial bones. In addition , Fac signal is detected in non-skeletal tissues: brain, whisker folli cles, lung, kidney, gut and stomach. Fac expression is high in progeni tor cell populations but is downregulated in differentiating cells tha t give rise to connective tissue. The pattern of Fac expression is con sistent with the skeletal and nonskeletal congenital abnormalities in FA patients. As well, expression in rapidly dividing progenitors is co nsistent with hypotheses regarding the nature of the basic defect in F A: a role of the protein in DNA repair or protection from oxygen toxic ity.