PDF(Pubmed)
Abstract：
Ferritin, the iron-storage protein, is composed of light- and heavy-chain subunits, encoded by FTL and FTH1, respectively. Heterozygous variants in FTL cause hereditary neuroferritinopathy, a type of neurodegeneration with brain iron accumulation (NBIA). Variants in FTH1 have not been previously associated with neurologic disease. We describe the clinical, neuroimaging, and neuropathology findings of five unrelated pediatric patients with de novo heterozygous FTH1 variants. Children presented with developmental delay, epilepsy, and progressive neurologic decline. Nonsense FTH1 variants were identified using whole-exome sequencing, with a recurrent variant (p.Phe171∗) identified in four unrelated individuals. Neuroimaging revealed diffuse volume loss, features of pontocerebellar hypoplasia, and iron accumulation in the basal ganglia. Neuropathology demonstrated widespread ferritin inclusions in the brain. Patient-derived fibroblasts were assayed for ferritin expression, susceptibility to iron accumulation, and oxidative stress. Variant FTH1 mRNA transcripts escape nonsense-mediated decay (NMD), and fibroblasts show elevated ferritin protein levels, markers of oxidative stress, and increased susceptibility to iron accumulation. C-terminal variants in FTH1 truncate ferritin\'s E helix, altering the 4-fold symmetric pores of the heteropolymer, and likely diminish iron-storage capacity. FTH1 pathogenic variants appear to act by a dominant, toxic gain-of-function mechanism. The data support the conclusion that truncating variants in the last exon of FTH1 cause a disorder in the spectrum of NBIA. Targeted knockdown of mutant FTH1 transcript with antisense oligonucleotides rescues cellular phenotypes and suggests a potential therapeutic strategy for this pediatric neurodegenerative disorder.
摘要：
铁蛋白,铁储存蛋白，由轻链和重链亚基组成，分别由FTL和FTH1编码。FTL中的杂合变体导致遗传性神经铁蛋白病，一种具有脑铁积累（NBIA）的神经变性。FTH1的变异以前与神经系统疾病无关。我们描述了临床，神经影像学,和神经病理学发现的五个无关的儿科患者从头杂合FTH1变异。出现发育迟缓的儿童，癫痫,和进行性神经系统衰退。使用全外显子组测序鉴定无义FTH1变体，具有循环变体(p.Phe171*）在四个无关的个体中确定。神经影像学显示弥漫性体积损失，桥脑小脑发育不全和基底节铁积累的特征。神经病理学显示大脑中广泛存在铁蛋白包涵体。测定患者来源的成纤维细胞的铁蛋白表达，对铁积累的敏感性，和氧化应激。变体FTH1mRNA转录本逃避无义介导的衰变（NMD），成纤维细胞显示铁蛋白蛋白水平升高，氧化应激的标志物，并增加了对铁积累的敏感性。FTH1截短铁蛋白E螺旋中的C末端变体，改变杂聚物的四重对称孔，并可能降低铁的储存能力。FTH1致病变异似乎是由显性的，毒性功能获得机制。数据支持以下结论:FTH1的最后外显子中的截短变体导致NBIA谱中的紊乱。用反义寡核苷酸靶向敲除突变型FTH1转录物拯救细胞表型,并提示这种小儿神经退行性疾病的潜在治疗策略。
