A novel mutation of HFE explains the classical phenotype of genetic hemochromatosis in a C282Y heterozygote

Gastroenterology. 1999 Jun;116(6):1409-12. doi: 10.1016/s0016-5085(99)70505-6.


Background & aims: Most patients with genetic hemochromatosis are homozygous for a single mutation of the HFE gene (C282Y). There is a second mutation, H63D, but its role in iron overload is less conclusive. The aim of this study was to investigate the basis of iron overload in a patient with classical hemochromatosis who was only heterozygous for C282Y and negative for H63D.

Methods: Genotype for the C282Y, H63D, and S65C mutations of HFE was determined in patient RFH, his family members, and 365 controls. The HFE gene was sequenced in patient RFH. Allele-specific reverse-transcription polymerase chain reaction was performed to investigate RNA splicing. Allele frequency was determined by allele-specific oligonucleotide hybridization.

Results: The patient is compound heterozygous for C282Y and a novel splice site mutation (IVS3 + 1G --> T). His sister has an identical genotype and elevated serum ferritin and transferrin saturation. The novel mutation functionally alters messenger RNA splicing, causing obligate skipping of exon 3. However, the IVS3 + 1G --> T mutation was found to be rare and was not detected in 630 control European chromosomes.

Conclusions: IVS3 + 1G --> T in the compound heterozygous state with C282Y results in iron overload that can progress to a severe phenotype of classical hemochromatosis. The demonstration of IVS3 +1G --> T highlights the possibility of other rare HFE mutations, particularly in C282Y heterozygotes with iron overload.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • DNA, Recombinant
  • Female
  • Gene Frequency
  • HLA Antigens / genetics*
  • Hemochromatosis / genetics*
  • Hemochromatosis Protein
  • Heterozygote*
  • Histocompatibility Antigens Class I / genetics*
  • Humans
  • Male
  • Membrane Proteins*
  • Middle Aged
  • Mutation / genetics*
  • Pedigree
  • Phenotype
  • RNA Splicing
  • RNA, Messenger / genetics


  • DNA, Recombinant
  • HFE protein, human
  • HLA Antigens
  • Hemochromatosis Protein
  • Histocompatibility Antigens Class I
  • Membrane Proteins
  • RNA, Messenger