Novel mutations in ATP13A2 associated with mixed neurological presentations and iron toxicity due to nonsense-mediated decay

Koray Kırımtay, Benan Temizci, Murat Gültekin, Zuhal Yapıcı, Arzu Karabay*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)


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.

Original languageEnglish
Article number147167
JournalBrain Research
Publication statusPublished - 1 Jan 2021

Bibliographical note

Publisher Copyright:
© 2020


This work was supported by Istanbul Technical University BAP 1359-39139 and The Scientific and Technological Research Council of Turkey (TUBITAK 112D053) SAN-TEZ 0415.STZ.2013-2 (for iPSC) to AK. We thank Elif Everest for the editing during the revision of the manuscript, and Prof. Dr. Alp Dincer for technical assistance for MRI.

FundersFunder number
TUBITAK112D053, SAN-TEZ 0415.STZ.2013-2
Türkiye Bilimsel ve Teknolojik Araştirma Kurumu
Istanbul Teknik ÜniversitesiBAP 1359-39139


    • ATP13A2
    • Iron
    • Kufor-Rakeb
    • NBIA
    • Nonsense-mediated decay


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