Clinical variability of Fanconi anemia (type C) results from expression of an amino terminal truncated Fanconi anemia complementation group C polypeptide with partial activity

Blood. 1996 May 15;87(10):4424-32.

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Cell Cycle
  • Cell Cycle Proteins*
  • Cell Line, Transformed
  • Codon / genetics
  • DNA-Binding Proteins*
  • Drug Resistance / genetics
  • Fanconi Anemia / classification
  • Fanconi Anemia / genetics*
  • Fanconi Anemia / pathology
  • Fanconi Anemia Complementation Group C Protein
  • Fanconi Anemia Complementation Group Proteins
  • Frameshift Mutation
  • Genetic Complementation Test
  • Herpesvirus 4, Human
  • Humans
  • Lymphocytes / metabolism
  • Mitomycin / pharmacology
  • Molecular Sequence Data
  • Nuclear Proteins*
  • Phenotype
  • Protein Biosynthesis
  • Proteins / chemistry
  • Proteins / genetics*
  • Proteins / metabolism
  • RNA Splicing
  • Sequence Deletion
  • Severity of Illness Index

Substances

  • Cell Cycle Proteins
  • Codon
  • DNA-Binding Proteins
  • FANCC protein, human
  • Fanconi Anemia Complementation Group C Protein
  • Fanconi Anemia Complementation Group Proteins
  • Nuclear Proteins
  • Proteins
  • Mitomycin