Human L-ferritin deficiency is characterized by idiopathic generalized seizures and atypical restless leg syndrome.
Human L-ferritin deficiency is characterized by idiopathic generalized seizures and atypical restless leg syndrome.
复制标题
DOI：
10.1084/jem.20130315
复制
发表时间：
2013-08-26
期刊：
影响因子：
--
通讯作者：
Levi S
中科院分区：
文献类型：
--
作者：
Cozzi A;Santambrogio P;Privitera D;Broccoli V;Rotundo LI;Garavaglia B;Benz R;Altamura S;Goede JS;Muckenthaler MU;Levi S
人L-铁蛋白缺乏导致细胞铁可用性降低和ROS产生增加，氧化蛋白增加，导致特发性全身性癫痫发作和非典型不宁腿综合征。广泛表达的铁储存蛋白铁蛋白在维持细胞铁稳态中起着重要作用。胞浆铁蛋白由重（H）和轻（L）亚基组成，其共组装成具有铁储存的内腔的中空球形壳。铁蛋白H链的铁氧化酶活性对于以其Fe 3+氧化态储存铁是至关重要的，而L链显示铁成核特性。我们描述了一个独特的情况下，一个23岁的女性患者受纯合子的功能丧失突变的L-铁蛋白基因，特发性全身性癫痫发作，和非典型不宁腿综合征（RLS）。我们发现，L链铁蛋白是检测不到的原代成纤维细胞从病人，因此铁蛋白只由H链。铁掺入FtH均聚物中的增加导致细胞铁可用性降低、胞质过氧化氢酶水平降低、SOD 1蛋白水平降低、ROS产生增强和氧化蛋白水平升高。重要的是，在成纤维细胞中观察到的关键表型特征也反映在来自患者成纤维细胞的重编程神经元中。我们的研究结果首次证明了L-铁蛋白缺乏症在人类中的病理生理后果，并有助于定义一种以特发性全身性癫痫发作和非典型RLS为特征的新疾病实体的概念。
Human L-ferritin deficiency causes reduced cellular iron availability and increased ROS production with enhanced oxidized proteins, which results in idiopathic generalized seizures and atypical restless leg syndrome. The ubiquitously expressed iron storage protein ferritin plays a central role in maintaining cellular iron homeostasis. Cytosolic ferritins are composed of heavy (H) and light (L) subunits that co-assemble into a hollow spherical shell with an internal cavity where iron is stored. The ferroxidase activity of the ferritin H chain is critical to store iron in its Fe3+ oxidation state, while the L chain shows iron nucleation properties. We describe a unique case of a 23-yr-old female patient affected by a homozygous loss of function mutation in the L-ferritin gene, idiopathic generalized seizures, and atypical restless leg syndrome (RLS). We show that L chain ferritin is undetectable in primary fibroblasts from the patient, and thus ferritin consists only of H chains. Increased iron incorporation into the FtH homopolymer leads to reduced cellular iron availability, diminished levels of cytosolic catalase, SOD1 protein levels, enhanced ROS production and higher levels of oxidized proteins. Importantly, key phenotypic features observed in fibroblasts are also mirrored in reprogrammed neurons from the patient’s fibroblasts. Our results demonstrate for the first time the pathophysiological consequences of L-ferritin deficiency in a human and help to define the concept for a new disease entity hallmarked by idiopathic generalized seizure and atypical RLS.
登录
查看更多内容
影响因子：
4.8
作者：
Earley, Christopher J.;Horska, Alena;Allen, Richard P.
通讯作者：
Allen, Richard P.
影响因子：
20.3
作者：
Cozzi, A;Corsi, B;Arosio, P
通讯作者：
Arosio, P
影响因子：
4.8
作者：
Allen, R
通讯作者：
Allen, R
影响因子：
4.8
作者：
Earley, Christopher J.;Barker, Peter B.;Allen, Richard P.
通讯作者：
Allen, Richard P.
影响因子：
6.1
作者：
Cozzi, Anna;Santambrogio, Paolo;Levi, Sonia
通讯作者：
Levi, Sonia