CLINICAL VARIABILITY OF FANCONI-ANEMIA (TYPE-C) RESULTS FROM EXPRESSION OF AN AMINO-TERMINAL TRUNCATED FANCONI-ANEMIA COMPLEMENTATION GROUP-C POLYPEPTIDE WITH PARTIAL ACTIVITY

Fanconi anemia (FA) is an autosomal recessive disease characterized by congenital anomalies, aplastic anemia, and cancer susceptibility. Mut ations within the FA complementation group C (FAC) gene account for ap proximately 14% of diagnosed FA cases, Two mutations, one in exon 1 (d elG322) and one in exon 4 (IVS4 + 4 A to T), account for 90% of known FAC mutations. The delG322 mutation results in a mild FA phenotype, wh ile the IVS4 + 4 A to T mutation results in a severe FA phenotype. To determine the molecular basis for this clinical variability, we analyz ed patient-derived cell lines for the expression of characteristic mut ant FAC polypeptides. All cell lines with the delG322 mutation express ed a 50-kD FAC polypeptide, FRP-50 (FAC-related protein), shown to be an amino terminal truncated isoform of FAC reinitiated at methionine 5 5, All cell lines with the IVS4 + 4 A to T mutation lacked FRP-50, Ove rexpression of a cDNA encoding FRP-50 in an FA(C) cell line resulted i n partial correction of mitomycin C sensitivity. In conclusion, expres sion of an amino terminal truncated FAC protein accounts, at least in part, for the clinical heterogeneity among FA(C) patients. (C) 1996 by The American Society of Hematology.