The FANC B, E, F and G Genes and Their Products

Abstract

The rare autosomal recessive syndrome Fanconi anemia (FA) leads to bone marrow failure and malignancy predisposition. Moreover, patients may present with several con-genital anomalies of the skeleton and genito-urinary tract, growth retardation and hyperpigmentation of the skin. Cells from FA patients are hypersensitive to crosslinking agents, and this hypersensitivity is the basis for a diagnostic test as well as enabling exploration of the genetic heterogeneity of the disease. ^''^'^^'^^ Starting with the considerable variation observed at both clinical and cellular level in FA syndrome, the presence of an underlying genetic heterogeneity was suspected. The existence of at least two complementation groups, named A and NonA, was determined by testing for complementation of the cellular and chromosomal hypersensitivity to mitomycin C in somatic cell hybrids constructed with lymphoblasts derived from four different FA patients.^^ Since that time, the number of FA complementation groups increased to four in 1992, concomi­ tant with the cloning of the first, FANCC,^^ to eight in 1997"^^ and it is presendy \2?^ FA-A is the most common FA subtype, accounting for about 65% of the affected individuals, FA-C and FA-G each represent less than 15% of the cases, the other groups being extremely rare. The genes coding for the groups A, C, Dl, D2, E, F, G and L have been cloned using several strategies, including functional cloning, chromosome walking, reverse genetics and direct se­ quencing of a potential gene.'^'^''^^'^^' 5,55,57 Complementation analysis and gene cloning, leading to the discovery of the pathological mutations of/vt/VCC genes, opened the possibility of determining the genotype/phenotype relationships and establishing a link between comple­ mentation group and the clinical outcome or the degree of hypersensitiv ity to cross-linking agent treatment. Although the diversity of the clinical traits is insufficient to class a patient in a defined complementation group, some significant differences have been reported in a large study that analyzed 245 FA patients from FA-A to FA-G complementation groups as well as mutations in FANCA and ivl/VCC genes. The results of that analysis indicated that (1) FA-G patients had a more severe pancytopenia and a higher risk of leukemia, (2) FA-D, FA-E and FA-F patients showed more somatic anomalies touching several different anatomic sites, in­ cluding the head, the skeleton, the kidneys, the urogenital trait, the cardiovascular and central nervous systems, and (3) FA-A patients homozygous for null mutations presented earlier onset of anemia.^ The cloning of FANCCy the first identified FA gene, closed a period during which the studies on FA essentially provided information concerning the phenotypic traits of the syn­ drome, at both clinical and cellular levels. The gene cloning opened the possibility to shed light on the molecular process(es) responsible for FA phenotypic heterogeneity. Unfortunately, the