14 - Hemochromatosis associated with hepcidin gene (HAMP) mutations

Summary

Hepcidin, an antimicrobial peptide produced by hepatocytes, is a central negative regulator of iron absorption that is encoded by the HAMP gene on chromosome 19q13 (Chapter 2). In humans, HAMP mutations account for a rare subtype of juvenile-onset hemochromatosis (OMIM #602390). Some patients have an autosomal recessive disorder associated with homozygosity for rare pathogenic HAMP mutations. Others have hemochromatosis phenotypes due to heterozygosity for a pathogenic HAMP mutation and co-inheritance of heterozygosity or homozygosity for HFE C282Y.

The precursor of hepcidin comprises 84 amino acids, from which 3 active peptides of 25, 22, and 20 amino acids, respectively, are produced by protease cleavage. The 25 and 20 amino acid peptides represent the major forms. Active forms of hepcidin contain numerous cysteines. Eight highly-conserved cysteine residues form four disulfide bonds, the critical basis of a rigid structure of the final peptide. The HAMP promoter contains consensus sequences for the transcription factor CCAAT/enhancer binding protein-α (CEBP/α) that confers liver tissue specificity. The HAMP promoter also responds to interleukin-6 (IL-6), and has a bone morphogenetic protein-responsive element (BMP-RE) that binds SMAD 1/5/8/4 protein complex. Hepcidin expression is decreased in HFE, “gain-of-function” SLC40A1, and TFR2 hemochromatosis, and increased in “loss-of-function” SLC40A1 hemochromatosis in the absence of HAMP mutations (Chapters 8, 12, 15). In experimental animals, hepcidin synthesis is increased by iron loading and inflammation and is inhibited by iron deficiency anemia and hypoxia.

Clinical and laboratory features

Patients who are homozygous for deleterious HAMP mutations have clinical phenotypes similar to those of patients with HJV hemochromatosis.