Premium
A Novel DCTN1 mutation with late‐onset parkinsonism and frontotemporal atrophy
Author(s) -
Araki Eiichi,
Tsuboi Yoshio,
Daechsel Justus,
Milnerwood Austen,
VilarinoGuell Carles,
Fujii Naoki,
Mishima Takayasu,
Oka Takayuki,
Hara Hideo,
Fukae Jiro,
Farrer Matthew J.
Publication year - 2014
Publication title -
movement disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.352
H-Index - 198
eISSN - 1531-8257
pISSN - 0885-3185
DOI - 10.1002/mds.25833
Subject(s) - parkinsonism , dynactin , frontotemporal dementia , atrophy , neurodegeneration , amyotrophic lateral sclerosis , proband , progressive supranuclear palsy , mutation , pathology , neuroscience , biology , medicine , genetics , disease , gene , dementia , protein subunit
Background Depression, parkinsonism, and hypoventilation (Perry syndrome) or familial motor neuron disease have been linked to mutations in dynactin P150 Glued ( 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 p150 Glued . 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