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A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron

¹ Dipartimento di Scienze Biomediche e Biotecnologie, Università di Cagliari, Italy
² Istituto di Neurogenetica e Neurofarmacologia, CNR, Cagliari
³ Ospedale Regionale Microcitemie, Clinica Pediatrica 2, Cagliari, Italy
⁴ Intrinsic LifeSciences, LLC, La Jolla, CA, USA
⁵ Department of Hematology, University of Pavia and Fondazione IRCCS Policlinico San Matteo, Pavia, Italy

Correspondence: Renzo Galanello, MD, Clinica Pediatrica 2, Ospedale Regionale Microcitemie, Università di Cagliari, via Jenner s.n., 09121 Cagliari, Italy E-mail:renzo.galanello{at}mcweb.unica.it

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.

Key words: anemia, hepcidin, iron deficiency, matriptase-2, serine protease, TMPRSS6.

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New and old players in the hepcidin pathway

Clara Camaschella, Laura Silvestri
Haematologica 2008 93: 1441-1444. [Full Text] [PDF]

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				C. Camaschella and L. Silvestri New and old players in the hepcidin pathway Haematologica, October 1, 2008; 93(10): 1441 - 1444. [Full Text] [PDF]