Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinaemia and cataract
Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinaemia and cataract
复制标题
显性高铁蛋白血症和白内障家族中 L 铁蛋白 mRNA 铁反应元件的突变
作者：
C. Beaumont;P. Leneuve;I. Devaux;J. Scoazec;M. Berthier;Marie;B. Grandchamp;D. Bonneau
铁蛋白是铁储存分子，其合成在翻译水平上由铁通过胞质蛋白铁调节蛋白（IRP）和存在于所有铁蛋白mRNA的5′非编码区的保守核苷酸基序-铁响应元件（IRE）1- 13之间的相互作用来调节。该区域形成茎环结构，当细胞的铁供应受到限制时，IRP与IRE结合并抑制铁蛋白合成4。铁蛋白是由一个24亚基蛋白质外壳周围的铁核心5。两种类型的亚基，H和L，分别由位于染色体11 q13和19q13.1上的两个基因编码6。这两种基因普遍表达，但转录调节介导的H/L mRNA比率7和异铁蛋白谱的组织特异性变化。我们现在报告鉴定一个单一的点突变，在IRE的L-铁蛋白mRNA的成员从一个家庭的影响，显性遗传性高铁蛋白血症和白内障。该突变由高度保守的CAGUGU基序中的A到G的变化组成，该基序构成IRE环并介导与IRP的高亲和力相互作用。我们发现，这种突变废除了IRP在体外的结合，并导致一个高的组成性的，调节不良的L-铁蛋白的合成在培养的淋巴母细胞建立从受影响的患者。据我们所知，这是影响IRP-IRE相互作用和铁介导的铁蛋白合成调节的第一个突变。我们认为组织中铁蛋白的过量产生是导致高铁蛋白血症的原因，而铁蛋白的细胞内积聚则导致白内障。
The synthesis of ferritin, the iron-storing molecule, is regulated at the translational level by iron through interaction between a cytoplasmic protein, iron regulatory protein (IRP), and a conserved nucleotide motif present in the 5′ non-coding region of all ferritin mRNAs — the iron responsive element (IRE)1–l3. This region forms a stem-loop structure and when the supply of iron to the cells is limited, the IRP is bound to IRE and represses ferritin synthesis4. Ferritin is composed of a 24-subunit protein shell surrounding an iron core5. The two types of subunit, H and L, are encoded by two genes located on chromosomes 11q13 and 19q13.1, respectively6. Both genes are ubiquitously expressed but trancriptional regulation mediates tissue-specific changes in the H/L mRNA ratio7 and isoferritin profiles. We now report the identification of a single point mutation in the IRE of the L-ferritin mRNA in members from a family affected with dominantly inherited hyperferritinaemia and cataract. This mutation consists of an A to G change in the highly conserved CAGUGU motif that constitutes the IRE loop and mediates the high-affinity interaction with the IRP. We show that this mutation abolishes the binding of IRP in vitro and leads to a high constitutive, poorly regulated L-ferritin synthesis in cultured lymphoblastoid cells established from affected patients. This is, to our knowledge, the first mutation affecting the IRP–IRE interaction and the iron-mediated regulation of ferritin synthesis. We suggest that excess production of ferritin in tissues is responsible for the hyperferritinaemia and that intracellular accumulation of ferritin leads to cataract.
铁调节元件 (IRE)：mRNA 非编码序列家族。
DOI：
10.1042/bj3040001
发表时间：
1994
期刊：
The Biochemical journal
影响因子：
--
作者：
Theil,EC
通讯作者：
Theil,EC
红白血病细胞分化中 NF-E2 活性的调节。
DOI：
10.1074/jbc.273.9.5358
发表时间：
1998
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Nagai,T;Igarashi,K;Akasaka,J;Furuyama,K;Fujita,H;Hayashi,N;Yamamoto,M;Sassa,S
通讯作者：
Sassa,S