Heterozygous nonsense variants in the ferritin heavy-chain gene FTH1 cause a neuroferritinopathy.
Heterozygous nonsense variants in the ferritin heavy-chain gene FTH1 cause a neuroferritinopathy.
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DOI：
10.1016/j.xhgg.2023.100236
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发表时间：
2023-10-12
期刊：
影响因子：
--
通讯作者：
Ortiz-Gonzalez, Xilma R.
中科院分区：
文献类型：
--
作者：
Shieh, Joseph T.;Tintos-Hernandez, Jesus A.;Murali, Chaya N.;Penon-Portmann, Monica;Flores-Mendez, Marco;Santana, Adrian;Bulos, Joshua A.;Du, Kang;Dupuis, Lucie;Damseh, Nadirah;Mendoza-Londono, Roberto;Berera, Camilla;Lee, Julieann C.;Phillips, Joanna J.;Alves, Cesar A. P. F.;Dmochowski, Ivan J.;Ortiz-Gonzalez, Xilma R.
铁蛋白是一种铁储存蛋白，由轻链和重链组成，分别由FTL和FTH1编码。FTL杂合变异导致遗传性神经铁蛋白病变，这是一种伴有脑铁积聚的神经退行性变(NBIA)。FTH1基因的变异此前并未与神经系统疾病相关。我们描述了5例无血缘关系的FTH1杂合子变异的儿科患者的临床、神经影像和神经病理学表现。儿童表现为发育迟缓、癫痫和进行性神经功能衰退。用全外显子组测序鉴定了无意义的FTH1变异，在四个无关的个体中发现了一个经常性的变异(p.Phe171∗)。神经影像显示弥漫性体积减少，桥小脑发育不良，以及基底节铁聚集。神经病理学显示脑内广泛存在铁蛋白包涵体。对患者来源的成纤维细胞进行铁蛋白表达、铁积累敏感性和氧化应激的检测。不同的FTH1基因转录本可以逃脱无意义介导的衰退(NMD)，成纤维细胞显示铁蛋白水平升高，氧化应激标志，并增加对铁积累的敏感性。FTH1的C末端变异会截断铁蛋白的E螺旋，改变杂多聚合物的4倍对称孔隙，并可能降低铁的储存能力。FTH1致病变异体似乎通过一种显性的、有毒的功能获得机制发挥作用。这些数据支持这样的结论，即FTH1最后一个外显子上的截断变异导致了NBIA谱的紊乱。用反义寡核苷酸靶向敲除突变的FTH1转录本可以挽救细胞表型，并为这种儿童神经退行性疾病提供了一种潜在的治疗策略。这份报告描述了编码铁蛋白重链的FTH1的从头变异如何与神经退行性变伴脑铁蓄积(NBIA)的一种儿科疾病有关。我们的数据表明，截断铁蛋白重链E螺旋的C末端变体会导致脑铁蛋白积聚和细胞氧化应激，反义寡核苷酸可以改善这一点。
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. This report describes how de novo variants in FTH1, encoding ferritin heavy chain, are linked to a pediatric disease in the spectrum of neurodegeneration with brain iron accumulation (NBIA). Our data suggest that C-terminal variants truncating the E helix of the ferritin heavy chain lead to brain ferritin accumulation and cellular oxidative stress, which can be ameliorated by antisense oligonucleotides.
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影响因子：
6.1
作者：
Maccarinelli F;Pagani A;Cozzi A;Codazzi F;Di Giacomo G;Capoccia S;Rapino S;Finazzi D;Politi LS;Cirulli F;Giorgio M;Cremona O;Grohovaz F;Levi S
通讯作者：
Levi S
影响因子：
3.1
作者：
Davalieva, Katarina;Kiprijanovska, Sanja;Plaseska-Karanfilska, Dijana
通讯作者：
Plaseska-Karanfilska, Dijana
影响因子：
3.5
作者：
Lee, J. -H.;Gregory, A.;Hayflick, S. J.
通讯作者：
Hayflick, S. J.
影响因子：
2.7
作者：
Ingrassia, Rosaria;Gerardi, Gianmario;Arosio, Paolo
通讯作者：
Arosio, Paolo
影响因子：
2.6
作者：
Kato, Junji;Kobune, Masayoshi;Niitsu, Yoshiro
通讯作者：
Niitsu, Yoshiro