A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron
A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron
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DOI：
10.3324/haematol.13342
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发表时间：
2008-10-01
期刊：
影响因子：
--
通讯作者：
Galanello, Renzo
中科院分区：
文献类型：
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作者：
Melis, Maria Antonietta;Cau, Milena;Galanello, Renzo
研究背景铁调素通过抑制巨噬细胞和肠细胞释放铁，在机体铁代谢中发挥重要作用。缺陷hepcidin合成导致铁负荷，而生产过剩的结果有缺陷的网状内皮铁的释放和铁的absorption.Design和MethodsWe研究了一个撒丁岛家庭，其中小红细胞贫血由于铁的吸收和利用缺陷是作为一个隐性遗传。五名成员表现出缺铁性贫血，口服铁无反应，仅部分反应肠外铁管理。为了研究已知的铁代谢相关基因的参与情况，我们用与这些基因接近的微卫星标记进行了连锁分析。之后，全基因组的搜索performed.ResultsNo连锁被发现患者的表型和几个已知的人类基因参与铁代谢（DMT 1，TF TFRC，ZIRTL，HAMP，HJV。通过微卫星和单核苷酸多态性进行的全基因组扫描显示，染色体22 q 12.3-13.1上的多点LOD得分为5.6，其中matriptase-2（也称为跨膜蛋白酶，丝氨酸6或TMPRSS 6）基因位于该染色体上。它的鼠对应物（Tmprss 6）最近被发现是一个途径，检测铁缺乏症和抑制铁调素生产的重要组成部分。TMPRSS 6的测序分析揭示了一个纯合的因果突变，预测剪接错误和截短的TMPRSS 6蛋白在受影响的成员。纯合子受试者血清和尿hepcidin.ConclusionsThe研究结果表明，观察到的TMPRSS 6突变导致过度生产的hepcidin，反过来，有缺陷的铁的吸收和利用水平不适当地升高。更一般地，他们在人类中证实了已经在小鼠中证实的间质蛋白酶-2对铁调素合成的抑制作用。
BackgroundHepcidin 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 MethodsWe 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.ResultsNo 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 22q 12.3-13.1, 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.ConclusionsThe 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.