Journal article
Novel mutations in ATP13A2 associated with mixed neurological presentations and iron toxicity due to nonsense-mediated decay
Brain research, v 1750, 147167
01 Jan 2021
PMID: 33091395
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Abstract
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 wholeexome 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.
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Details
- Title
- Novel mutations in ATP13A2 associated with mixed neurological presentations and iron toxicity due to nonsense-mediated decay
- Creators
- Koray Kirimtay - Istanbul Tech Univ, Dept Mol Biol & Genet, TR-34469 Istanbul, TurkeyBenan Temizci - Istanbul Technical UniversityMurat Gultekin - Erciyes UniversityZuhal Yapici - Istanbul UniversityArzu Karabay - Istanbul Technical University
- Publication Details
- Brain research, v 1750, 147167
- Publisher
- Elsevier
- Number of pages
- 10
- Grant note
- BAP 1359-39139 / Istanbul Technical University (TUBITAK 112D053) SAN-TEZ 0415.STZ.2013-2 / Scientific and Technological Research Council of Turkey; Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurobiology and Anatomy
- Web of Science ID
- WOS:000596934400004
- Scopus ID
- 2-s2.0-85093933084
- Other Identifier
- 991022018186804721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Neurosciences