Characterization of DCTN1 genetic variability in neurodegeneration.
OBJECTIVE
Recently, mutations in DCTN1 were found to cause Perry syndrome, a parkinsonian disorder with TDP-43-positive pathology. Previously, mutations in DCTN1 were identified in a family with lower motor neuron disease, in amyotrophic lateral sclerosis (ALS), and in a family with ALS/frontotemporal dementia (FTD), suggesting a central role for DCTN1 in neurodegeneration.


METHODS
In this study we sequenced all DCTN1 exons and exon-intron boundaries in 286 samples diagnosed with Parkinson disease (PD), frontotemporal lobar degeneration (FTLD), or ALS.


RESULTS
This analysis revealed 36 novel variants (9 missense, 5 silent, and 22 noncoding). Segregation analysis in families and association studies in PD, FTLD, and ALS case-control series did not identify any variants segregating with disease or associated with increased disease risk.


CONCLUSIONS
This study suggests that pathogenic mutations in DCTN1 are rare and do not play a common role in the development of Parkinson disease, frontotemporal lobar degeneration, or amyotrophic lateral sclerosis.
Vilariño-Güell
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Molecular Genetics Laboratory and Core, Morris K. Udall Parkinson's Disease Research Center of Excellence, Mayo Clinic, Department of Neuroscience, 4500 San Pablo Road, Jacksonville, FL 32224, USA. VilarinoGuell.Carles@mayo.edu
Wider
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Soto-Ortolaza
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AI
Cobb
S A
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Kachergus
J M
JM
Keeling
B H
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Dachsel
J C
JC
Hulihan
M M
MM
Dickson
D W
DW
Wszolek
Z K
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Uitti
R J
RJ
Graff-Radford
N R
NR
Boeve
B F
BF
Josephs
K A
KA
Miller
B
B
Boylan
K B
KB
Gwinn
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K
Adler
C H
CH
Aasly
J O
JO
Hentati
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Destée
A
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Krygowska-Wajs
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Chartier-Harlin
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Ross
O A
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Rademakers
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Farrer
M J
MJ
D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D003704:Dementia / Q000235:genetics*; D000072159:Dynactin Complex; D005091:Exons / Q000235:genetics; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics*
C000606360:DCTN1 protein, human; D004268:DNA-Binding Proteins; D000072159:Dynactin Complex; D005819:Genetic Markers; D008869:Microtubule-Associated Proteins