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Novel mutations in ATP13A2 associated with mixed neurological presentations and iron toxicity due to nonsense-mediated decay
Brain Research ( IF 2.9 ) Pub Date : 2020-10-19 , DOI: 10.1016/j.brainres.2020.147167
Koray Kırımtay 1 , Benan Temizci 1 , Murat Gültekin 2 , Zuhal Yapıcı 3 , Arzu Karabay 1
Affiliation  

Background

Kufor-Rakeb Syndrome (KRS) is an autosomal recessive disease characterized by Parkinsonism, pyramidal signs, dementia, and supranuclear gaze palsy. KRS is caused by mutations in ATP13A2 producing a transmembrane protein responsible for the regulation of intracellular inorganic cations.

Objective

Two siblings born to a Turkish family of consanguineous marriage had mixed neurological presentations with the presence of hypointense images on T2-weighted MRI and were pre-diagnosed as having autosomal recessive spastic paraparesis or ataxia. We aimed to identify the disease-causing mutation by whole-exome sequencing and elucidate the underlying molecular mechanism of the causative mutation.

Methods

Prussian blue staining was conducted for the detection of cellular iron accumulation. Disease-causing mutation in ATP13A2 was detected by whole-exome sequencing. Expression levels of ATP13A2 mRNA and protein were assessed by qRT-PCR and Western Blot.

Results

Iron deposits in the patients’ fibroblasts were detected by Prussian blue staining. Novel homozygous mutation c.1422_1423del:p.P474fs was detected in the ATP13A2. As this mutation caused a premature termination codon (PTC), the expression of mutant ATP13A2 mRNA through qRT-PCR analysis was found to be degraded by nonsense-mediated decay and this prevented the expression of ATP13A2 protein in the patients’ fibroblasts.

Conclusions

Novel frameshift mutation causing a PTC in ATP13A2 lead to degradation of ATP13A2 mRNA by NMD. Iron accumulation due to the absence of ATP13A2 protein in the patient’s fibroblasts and hypointense areas on T2-weighted images may expand the spectrum of KRS to consider it as neurodegeneration with brain iron accumulation disorders.



中文翻译:

ATP13A2 的新突变与混合神经学表现和无义介导的衰变引起的铁毒性相关

背景

Kufor-Rakeb 综合征 (KRS) 是一种常染色体隐性遗传疾病,其特征是帕金森病、锥体体征、痴呆和核上性凝视麻痹。KRS 是由 产生跨膜蛋白的ATP13A2突变引起的,该蛋白负责调节细胞内无机阳离子。

客观的

土耳其近亲婚姻家庭所生的两个兄弟姐妹神经系统表现混合,T2 加权 MRI 显示低信号,并被预先诊断为常染色体隐性痉挛性下肢轻瘫或共济失调。我们旨在通过全外显子组测序鉴定致病突变并阐明致病突变的潜在分子机制。

方法

进行普鲁士蓝染色以检测细胞铁积累。 通过全外显子组测序检测到ATP13A2 中的致病突变 。通过 qRT-PCR 和蛋白质印迹评估ATP13A2 mRNA 和蛋白质的表达水平。

结果

通过普鲁士蓝染色检测到患者成纤维细胞中的铁沉积。在 ATP13A2 中检测到新的纯合突变 c.1422_1423del:  p.P474fs。由于该突变导致过早终止密码子 (PTC),通过 qRT-PCR 分析发现突变体ATP13A2 mRNA 的表达被无义介导的衰变降解,这阻止了患者成纤维细胞中 ATP13A2 蛋白的表达。

结论

ATP13A2 中引起 PTC 的新型移码突变导致ATP13A2 mRNA 被 NMD降解。由于患者的成纤维细胞中缺乏 ATP13A2 蛋白而导致的铁积累和 T2 加权图像上的低信号区域可能会扩大 KRS 的范围,将其视为具有脑铁积累障碍的神经变性。

更新日期:2020-10-30
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