Autosomal-dominant Hemochromatosis Is Associated With a Mutation in the Ferroportin (SLC11A3) Gene

J Clin Invest. 2001 Aug;108(4):619-23. doi: 10.1172/JCI13468.

Abstract

Hemochromatosis is a progressive iron overload disorder that is prevalent among individuals of European descent. It is usually inherited in an autosomal-recessive pattern and associated with missense mutations in HFE, an atypical major histocompatibility class I gene. Recently, we described a large family with autosomal-dominant hemochromatosis not linked to HFE and distinguished by early iron accumulation in reticuloendothelial cells. Through analysis of a large pedigree, we have determined that this disease maps to 2q32. The gene encoding ferroportin (SLC11A3), a transmembrane iron export protein, lies within a candidate interval defined by highly significant lod scores. We show that the iron-loading phenotype in autosomal-dominant hemochromatosis is associated with a nonconservative missense mutation in the ferroportin gene. This missense mutation, converting alanine to aspartic acid at residue 77 (A77D), was not seen in samples from 100 unaffected control individuals. We propose that partial loss of ferroportin function leads to an imbalance in iron distribution and a consequent increase in tissue iron accumulation.

Publication types

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

MeSH terms

  • Amino Acid Substitution*
  • Animals
  • Carrier Proteins / genetics*
  • Carrier Proteins / physiology
  • Cation Transport Proteins*
  • Chromosomes, Human, Pair 2 / genetics*
  • Codon / genetics
  • Exons / genetics
  • Female
  • Genes, Dominant*
  • Genetic Heterogeneity
  • HLA Antigens / genetics
  • Hemochromatosis / epidemiology
  • Hemochromatosis / genetics*
  • Hemochromatosis Protein
  • Histocompatibility Antigens Class I / genetics
  • Homeostasis
  • Humans
  • Iron / metabolism
  • Iron Overload / genetics
  • Iron Overload / metabolism
  • Italy / epidemiology
  • Lod Score
  • Male
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics*
  • Membrane Proteins / physiology
  • Mice
  • Mononuclear Phagocyte System / metabolism*
  • Mutation, Missense*
  • Pedigree
  • Phenotype
  • Receptors, Transferrin / genetics

Substances

  • Carrier Proteins
  • Cation Transport Proteins
  • Codon
  • HFE protein, human
  • HLA Antigens
  • Hemochromatosis Protein
  • Hfe protein, mouse
  • Histocompatibility Antigens Class I
  • Membrane Proteins
  • Receptors, Transferrin
  • TFR2 protein, human
  • TFR2 protein, mouse
  • metal transporting protein 1
  • Iron