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A Novel DCTN1 mutation with late-onset parkinsonism and frontotemporal atrophy

Authors


  • Relevant conflicts of interest/financial disclosures: Nothing to report.

  • Funding agencies: This research was undertaken, in part, thanks to funding from the Canada Excellence Research Chairs program (to M.J.F.). In addition, Leading Edge Endowment Funds provided by the Province of British Columbia, Life Labs, and Genome BC support the Dr. Donald Rix BC Leadership Chair (to M.J.F.).

  • Full financial disclosures and author roles may be found in the online version of this article.

ABSTRACT

Background

Depression, parkinsonism, and hypoventilation (Perry syndrome) or familial motor neuron disease have been linked to mutations in dynactin P150Glued (DCTN1).

Methods

We employed genealogic, clinical, neurologic, and MRI investigations, as well as analysis of genes implicated in parkinsonism. Cellular transfection, immunocytochemistry, and immunoprecipitation analysis of wild-type (WT) and mutant DCTN1 were also performed.

Results

A novel heterozygous mutation, DCTN1 c.156T>G, encoding p.Phe52Leu, segregates with parkinsonism in a Japanese family. The substitution was not observed in affected probands with familial parkinsonism or control subjects and is evolutionarily conserved. In contrast to Perry syndrome, affected carriers have late-onset disease and slower progression, with frontotemporal atrophy revealed by MRI. In vitro studies suggest the mutant protein has impaired microtubule binding, compared to WT dynactin p150Glued.

Conclusions

DCTN1 mutations may contribute to disparate neurodegenerative diagnoses, including familial motor neuron disease, parkinsonism, and frontotemporal atrophy, and further studies of dynactin-mediated cargo transport may prove insightful. © 2014 International Parkinson and Movement Disorder Society

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