Genetics

Mutation in the HFE gene located on chromosome 6 is the principle gene defect that increases the risk of developing haemochromatosis

• this mutation causes the substitution of tyrosine for cysteine at amino acid position 282 of the protein product (C282Y)
  • account for 80%-85% of typical patients with HH
• two more mutations have been identified - aspartate is substituted for histidine at amino acid position 63 (H63D) and cysteine is substituted for serine at amino acid position 65 (S65C)
  • are not generally associated with iron loading unless occurring as a compound heterozygote (C282Y/H63D or C282Y/ S65C) (1,2)

Other inherited forms known as non HFE related hereditary hemachromatosis (HH) encompasses all genetic hemachromatosis unrelated to HFE mutations.

• transferrin receptor 2 (TfR2)-associated haemochromatosis
  • also called “type 3 haemochromatosis”
  • caused by mutations in the genes for transferrin receptor 2 (TfR2)
  • autosomal recessive form which is clinically similar to HFE related HH
  • may present early in life.
• juvenile haemochromatosis
  • also known as “type 2 haemochromatosis”
  • mutations in two different genes results in two forms of juvenile HH
    • type 2A - mutation in the hemojuvelin (HJV) gene on chromosome 1q – most common form
    • type 2B - mutations in the hepcidin gene (HAMP)
• mutations in the genes for ferroportin (SLC40A1)
  • improperly called “type 4 haemochromatosis”
  • inherited in a dominant fashion (1,2)

Reference:

• (1) Bacon BR et al. Diagnosis and management of hemochromatosis: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011l;54(1):328-43
• (2) European School of Haematology (ESH). ESH Handbook on Disorders of Iron Metabolism (2009)