Disease relevance of HAMP

• Hepcidin was found to be suppressed in patients with thalassemia syndromes and congenital dyserythropoietic anemia type 1 and was undetectable in patients with juvenile hemochromatosis with HAMP mutations [1].
• BACKGROUND/AIMS: In HFE-related hereditary hemochromatosis an inappropriately low hepatic expression of the iron-regulatory peptide hepcidin (encoded by HAMP) has been suggested to cause iron overload [2].
• Recently hepcidin antimicrobial peptide has emerged as the hormone that links the type II acute phase response to iron handling and erythropoiesis [3].
• We explored this mechanism in vitro and in vivo using HAMP domain fusions with a mycobacterial adenylyl cyclase and an E. coli chemotaxis receptor [4].
• In radial diffusion assays, Gram-positive Bacillus megaterium, Bacillus subtilis, Micrococcus luteus, Staphylococcus carnosus, and Gram-negative Neisseria cinerea as well as the yeast Saccharomyces cerevisiae dose-dependently exhibited sensitivity upon treatment with synthetic LEAP-1 [5].

High impact information on HAMP

• Hepcidin, a peptide hormone (HAMP; OMIM 606464), seems to act in the same regulatory pathway as HFE [6].
• Although expression of mouse Hamp is normally greater during iron overload, Hfe-/- mice have inappropriately low expression of Hamp [6].
• Increased serum concentrations of the hepcidin precursor prohepcidin were paralleled by a decreased expression of the iron exporter ferroportin in circulating monocytes of ACD patients [7].
• It is most often caused by mutations in the HJV gene and rarely in the HAMP gene [8].
• These results revealed that mutations in HAMP might increase the phenotypic expression of the pC282Y/pC282Y genotype [9].

Chemical compound and disease context of HAMP

• In intact animals, iron overload or the injection of lipopolysaccharide (LPS) stimulates transcription of HAMP, the gene that encodes hepcidin [10].

Biological context of HAMP

• INTERPRETATION: Lack of HAMP upregulation in HFE-associated haemochromatosis despite significant hepatic iron loading indicates that HFE plays an important part in the regulation of hepcidin expression in response to iron overload [11].
• We propose that the phenotype of C282Y heterozygotes and homozygotes may be modified by heterozygosity for mutations which disrupt the function of hepcidin in iron homeostasis, with the severity of iron overload corresponding to the severity of the HAMP mutation [12].
• In family A, the proband has a JH phenotype and is heterozygous for C282Y and a novel HAMP mutation Met50del IVS2+1(-G) [12].
• From a cohort of 31 patients with at least one chromosome lacking an HFE mutation, we further identified 4 males carrying a heterozygous HAMP mutation (pR59G or pG71D) [9].
• Sequence analysis of HAMP revealed homozygosity for amino acid substitution C78T due to a c.233G > A mutation [13].

Anatomical context of HAMP

• RECENT FINDINGS: Hepcidin antimicrobial peptide likely modulates iron transport from macrophages and enterocytes to red blood cell precursors as a consequence of its interaction with SLC40A1/ferroportin, the only known transporter that facilitates iron egress [3].
• Regulatory effects of tumor necrosis factor-alpha and interleukin-6 on HAMP expression in iron loaded rat hepatocytes [14].
• We found the iron regulatory hormone hepcidin (HAMP) is also produced by alveolar macrophages [15].
• Distinct but overlapping profiles of expression were detected in cornea and conjunctiva, with expression of beta-defensin-3 and -4 and LEAP1 and -2 most common in cultured corneal epithelia [16].
• The results indicate that Hepc released by HepG2 inhibited apical iron uptake by Caco-2 cells, probably by inhibiting the expression of the apical transporter DMT1 [17].

Associations of HAMP with chemical compounds

• HAMP domains connect extracellular sensory with intracellular signaling domains in over 7500 proteins, including histidine kinases, adenylyl cyclases, chemotaxis receptors, and phosphatases [4].
• In the presence of serum, tumor necrosis factor-alpha, lipopolysaccharide and interleukin-6 increased HAMP expression in hepatocytes from both control and iron-loaded rats [14].
• Desferrioxamine and ferric ammonium citrate decreased HAMP gene expression [14].
• RESULTS: Hepatocytes from control rats increased their HAMP expression during culturing, whereas the opposite was seen in hepatocytes from carbonyl-iron loaded animals [14].
• Previous studies reported mutations in the HAMP domain that abolished FAD binding to the PAS domain [18].

Other interactions of HAMP

• RESULTS: The overall level of hepatic HAMP expression in human and murine HFE-related hemochromatosis is impaired but can still be modulated by iron stores [2].
• Moreover, we demonstrate an HFE-independent correlation between the expression of HAMP and TFR2 in mouse and human livers [2].
• Juvenile GH is a rare condition related principally to mutations of the HJV gene coding for hemojuvelin, and rarely to mutations of the HAMP gene coding for hepcidin [19].
• Ferroportin and TFR2 mutations also cause HH, and two HAMP mutations have recently been reported that causes juvenile haemochromatosis (JH) in the homozygous state [12].
• IL-1 and IL-6, which are important in HAMP augmentation in hepatocytes, also did not affect HAMP expression in alveolar macrophages [15].

Analytical, diagnostic and therapeutic context of HAMP

• Animal models indicate that the antimicrobial peptide hepcidin (HAMP; OMIM 606464) is probably a key regulator of iron absorption in mammals [20].
• In this study, using random and site-directed mutagenesis, we identified the distal helix, AS-2, as the component of the HAMP domain that stabilizes FAD binding [18].
• By electrophoretic mobility shift assay we demonstrated that one putative C/EBP element found in the human HEPC promoter (-250/-230) predominantly bound C/EBPalpha from rat liver nuclear extracts [21].
• RESULTS: A total of 164 maxillary molars were examined, providing 328 interproximal furcations; 111 (33.8%) furcations were determined at surgical debridement to have a furcation invasion of Hamp degree 1 or greater [22].
• The authors conclude that PLTR from a living donor is a promising therapeutic alternative to liver transplantation from a cadaver [23].

References