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. DESIGN AND 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.
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. DESIGN AND 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: Irene Pichler; Cosetta Minelli; Serena Sanna; Toshiko Tanaka; Christine Schwienbacher; Silvia Naitza; Eleonora Porcu; Cristian Pattaro; Fabio Busonero; Alessandra Zanon; Andrea Maschio; Scott A Melville; Maria Grazia Piras; Dan L Longo; Jack Guralnik; Dena Hernandez; Stefania Bandinelli; Elmar Aigner; Anthony T Murphy; Victor Wroblewski; Fabio Marroni; Igor Theurl; Carsten Gnewuch; Eric Schadt; Manfred Mitterer; David Schlessinger; Luigi Ferrucci; Derrick R Witcher; Andrew A Hicks; Günter Weiss; Manuela Uda; Peter P Pramstaller Journal: Hum Mol Genet Date: 2010-12-28 Impact factor: 6.150
Authors: Toni M Antalis; Marguerite S Buzza; Kathryn M Hodge; John D Hooper; Sarah Netzel-Arnett Journal: Biochem J Date: 2010-06-15 Impact factor: 3.857
Authors: Paul J Schmidt; Iva Toudjarska; Anoop K Sendamarai; Tim Racie; Stuart Milstein; Brian R Bettencourt; Julia Hettinger; David Bumcrot; Mark D Fleming Journal: Blood Date: 2012-12-06 Impact factor: 22.113