title: A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron.
abstract: BACKGROUND
  Hepcidin plays a key role in body iron metabolism by preventing the release of iron from macrophages and intestinal cells. Defective hepcidin synthesis causes iron loading, while overproduction results in defective reticuloendothelial iron release and iron absorption.
  
  
  METHODS
  We studied a Sardinian family in which microcytic anemia due to defective iron absorption and utilization is inherited as a recessive character. Five members showed iron deficiency anemia that was not responsive to oral iron and only partially responsive to parenteral iron administration. To investigate the involvement of known genes implicated in iron metabolism we carried out linkage analysis with microsatellite markers mapping close to these genes. Afterwards, a genome-wide search was performed.
  
  
  RESULTS
  No linkage was found between the phenotype of the patients and several known human genes involved in iron metabolism (DMT1, TF, TFRC, ZIRTL, HAMP, HJV). Genome-wide scanning by microsatellites and single nucleotide polymorphisms showed a multipoint LOD score of 5.6 on chromosome 22q12.3-13.1, where the matriptase-2 (also known as transmembrane protease, serine 6 or TMPRSS6) gene is located. Its murine counterpart (Tmprss6) has recently been found to be an essential component of a pathway that detects iron deficiency and suppresses hepcidin production. Sequencing analysis of TMPRSS6 revealed a homozygous causal mutation, predicting a splicing error and a truncated TMPRSS6 protein in affected members. Homozygous subjects had inappropriately elevated levels of serum and urinary hepcidin.
  
  
  CONCLUSIONS
  The findings of this study suggest that the observed TMPRSS6 mutation leads to overproduction of hepcidin and, in turn, to defective iron absorption and utilization. More generally, they confirm in humans the inhibitory effect of matriptase-2 on hepcidin synthesis already demonstrated in mice.
authors.affiliation: Dipartimento di Scienze Biomediche e Biotecnologie, Università di Cagliari, Cagliari, Italy.
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Melis
authors.forename: Milena
authors.initials: M
authors.lastname: Cau
authors.forename: Rita
authors.initials: R
authors.lastname: Congiu
authors.forename: Gabriella
authors.initials: G
authors.lastname: Sole
authors.forename: Susanna
authors.initials: S
authors.lastname: Barella
authors.forename: Antonio
authors.initials: A
authors.lastname: Cao
authors.forename: Mark
authors.initials: M
authors.lastname: Westerman
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
authors.forename: Renzo
authors.initials: R
authors.lastname: Galanello
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D018798:Anemia, Iron-Deficiency / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis*; D001483:Base Sequence; D002462:Cell Membrane / Q000201:enzymology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006454:Hemoglobins / Q000378:metabolism; D064451:Hepcidins; D006801:Humans; D007501:Iron / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
chemical_list: D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D006454:Hemoglobins; D064451:Hepcidins; D008565:Membrane Proteins; D007501:Iron; D012697:Serine Endopeptidases; C504318:TMPRSS6 protein, human