title: Severe hemochromatosis in a Portuguese family associated with a new mutation in the 5'-UTR of the HAMP gene.
abstract: Juvenile hereditary hemochromatosis is a genetically heterogeneous disorder transmitted as an autosomal recessive trait. It is most often caused by mutations in the HJV gene and rarely in the HAMP gene. Hepcidin is considered to constitute a negative regulator of iron absorption, and its production is increased in inflammatory states and iron overload. We report the detection of a new mutation in the HAMP gene leading to juvenile hemochromatosis in 2 members of a Portuguese family. The mutation lies in the 5'-UTR (untranslated region) of the gene and creates a new initiation codon in the context of a Kozak sequence. We found no trace of hepcidin protein in the patients' urine, suggesting that ribosomes select the mutant initiation codon for translation. The decrease of hepcidin production would thus lead to increased iron absorption, resulting in iron deposition in parenchymal tissues. Phlebotomy therapy of the 2 patients resulted in impressive clinical improvement.
authors.affiliation: Division of Hematology, University Hospital, Geneva, Switzerland. thomas.matthes@hcuge.ch
authors.forename: Thomas
authors.initials: T
authors.lastname: Matthes
authors.forename: Patricia
authors.initials: P
authors.lastname: Aguilar-Martinez
authors.forename: Loredana
authors.initials: L
authors.lastname: Pizzi-Bosman
authors.forename: Régis
authors.initials: R
authors.lastname: Darbellay
authors.forename: Laura
authors.initials: L
authors.lastname: Rubbia-Brandt
authors.forename: Emilio
authors.initials: E
authors.lastname: Giostra
authors.forename: Martine
authors.initials: M
authors.lastname: Michel
authors.forename: Tomas
authors.initials: T
authors.lastname: Ganz
authors.forename: Photis
authors.initials: P
authors.lastname: Beris
mesh_terms: D020121:5' Untranslated Regions; D000328:Adult; D023181:Antimicrobial Cationic Peptides / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D001483:Base Sequence; D015153:Blotting, Western; D003062:Codon; D004247:DNA / Q000737:chemistry; D018076:DNA, Complementary / Q000378:metabolism; D005192:Family Health; D005260:Female; D058851:GPI-Linked Proteins; D006432:Hemochromatosis / Q000208:ethnology / Q000235:genetics*; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D006801:Humans; D007249:Inflammation; D007501:Iron / Q000737:chemistry / Q000378:metabolism; D019190:Iron Overload; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D011174:Portugal; D014176:Protein Biosynthesis; D012313:RNA / Q000737:chemistry; D013997:Time Factors
chemical_list: D020121:5' Untranslated Regions; D023181:Antimicrobial Cationic Peptides; D003062:Codon; D018076:DNA, Complementary; D058851:GPI-Linked Proteins; C578702:HAMP protein, human; C481006:HJV protein, human; D000071020:Hemochromatosis Protein; D064451:Hepcidins; D008565:Membrane Proteins; D012313:RNA; D004247:DNA; D007501:Iron