Partial correction of a severe molecular defect in hemophilia A, because of errors during expression of the factor VIII gene

Am J Hum Genet. 1997 Mar;60(3):565-73.


Although the molecular defect in patients in a Japanese family with mild to moderately severe hemophilia A was a deletion of a single nucleotide T within an A8TA2 sequence of exon 14 of the factor VIII gene, the severity of the clinical phenotype did not correspond to that expected of a frameshift mutation. A small amount of functional factor VIII protein was detected in the patient's plasma. Analysis of DNA and RNA molecules from normal and affected individuals and in vitro transcription/translation suggested a partial correction of the molecular defect, because of the following: (i) DNA replication/RNA transcription errors resulting in restoration of the reading frame and/or (ii) "ribosomal frameshifting" resulting in the production of normal factor VIII polypeptide and, thus, in a milder than expected hemophilia A. All of these mechanisms probably were promoted by the longer run of adenines, A10 instead of A8TA2, after the delT. Errors in the complex steps of gene expression therefore may partially correct a severe frameshift defect and ameliorate an expected severe phenotype.

Publication types

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

MeSH terms

  • DNA Replication
  • Exons
  • Factor VIII / analysis
  • Factor VIII / genetics*
  • Female
  • Frameshift Mutation*
  • Frameshifting, Ribosomal
  • Gene Expression
  • Hemophilia A / genetics*
  • Humans
  • Male
  • Pedigree
  • Protein Biosynthesis
  • Reading Frames
  • Templates, Genetic
  • Transcription, Genetic


  • Factor VIII