title: Clinical variability of Fanconi anemia (type C) results from expression of an amino terminal truncated Fanconi anemia complementation group C polypeptide with partial activity.
abstract: Fanconi anemia (FA) is an autosomal recessive disease characterized by congenital anomalies, aplastic anemia, and cancer susceptibility. Mutations within the FA complementation group C (FAC) gene account for approximately 14% of diagnosed FA cases. Two mutations, one in exon 1 (delG322) 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, while the IVS4 + 4 A to T mutation results in severe FA phenotype. To determine the molecular basis for this clinical variability, we analyzed patient-derived cell lines for the expression of characteristic mutant FAC polypeptides. All cell lines with the delG322 mutation expressed a 50-kD FAC polypeptides, FRP-50 (FAC-related protein), shown to be an amino terminal truncated isoform of FAC reinitiated at methionine 55. All cell lines with the IVS4 + 4 A to T mutation lacked FRP-50. Overexpression of a cDNA encoding FRP-50 in an FA(C) cell line resulted in partial correction of mitomycin C sensitivity. In conclusion, expression of an amino terminal truncated FAC protein accounts, at least in part, for the clinical heterogeneity among FA(C) patients.
authors.affiliation: Division of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: T
authors.initials: T
authors.lastname: Yamashita
authors.forename: N
authors.initials: N
authors.lastname: Wu
authors.forename: G
authors.initials: G
authors.lastname: Kupfer
authors.forename: C
authors.initials: C
authors.lastname: Corless
authors.forename: H
authors.initials: H
authors.lastname: Joenje
authors.forename: M
authors.initials: M
authors.lastname: Grompe
authors.forename: A D
authors.initials: AD
authors.lastname: D'Andrea
mesh_terms: D001483:Base Sequence; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002461:Cell Line, Transformed; D003062:Codon / Q000235:genetics; D004268:DNA-Binding Proteins; D004351:Drug Resistance / Q000235:genetics; D005199:Fanconi Anemia / Q000145:classification / Q000235:genetics* / Q000473:pathology; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D016368:Frameshift Mutation; D005816:Genetic Complementation Test; D004854:Herpesvirus 4, Human; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism; D016685:Mitomycin / Q000494:pharmacology; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D010641:Phenotype; D014176:Protein Biosynthesis; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012326:RNA Splicing; D017384:Sequence Deletion; D012720:Severity of Illness Index
chemical_list: D018797:Cell Cycle Proteins; D003062:Codon; D004268:DNA-Binding Proteins; C497651:FANCC protein, human; D052218:Fanconi Anemia Complementation Group C Protein; D051856:Fanconi Anemia Complementation Group Proteins; D009687:Nuclear Proteins; D011506:Proteins; D016685:Mitomycin