Analysis of nuclear export sequence regions of FUS-Related RNA-binding proteins in essential tremor.
OBJECTIVE
Genes encoding RNA-binding proteins, including FUS and TDP43, play a central role in different neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Recently, a mutation located in the nuclear export signal (NES) of the FUS gene has been reported to cause an autosomal dominant form of familial Essential tremor.


METHODS
We sequenced the exons coding the NES domains of five RNA-binding proteins (TARDBP, hnRNPA2B1, hnRNPA1, TAF15 and EWSR1) that have been previously implicated in neurodegeneration in a series of 257 essential tremor (ET) cases and 376 healthy controls. We genotyped 404 additional ET subjects and 510 healthy controls to assess the frequency of the EWSR1 p.R471C substitution.


RESULTS
We identified a rare EWSR1 p.R471C substitution, which is highly conserved, in a single subject with familial ET. The pathogenicity of this substitution remains equivocal, as DNA samples from relatives were not available and the genotyping of 404 additional ET subjects did not reveal any further carriers. No other variants were observed with significant allele frequency differences compared to controls in the NES coding regions.


CONCLUSIONS
The present study demonstrates that the NES domains of RNA-binding proteins are highly conserved. The role of the EWSR1 p.R471C substitution needs to be further evaluated in future studies.
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America.
Oswaldo
O
Lorenzo-Betancor
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America.
Kotaro
K
Ogaki
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America.
Alexandra
A
Soto-Ortolaza
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America.
Catherine
C
Labbé
Djavad Mowafaghian Center for Brain Heath, Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
Carles
C
Vilariño-Güell
Division of Neurology, University of Saskatchewan and Saskatoon Health Region, Saskatoon, Canada.
Alex
A
Rajput
Division of Neurology, University of Saskatchewan and Saskatoon Health Region, Saskatoon, Canada.
Ali H
AH
Rajput
Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain; Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Barcelona, Spain.
Pau
P
Pastor
Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
Sara
S
Ortega
Neurogenetics Laboratory, Division of Neurosciences, Center for Applied Medical Research, University of Navarra School of Medicine, Pamplona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, CIBERNED, Instituto de Salud Carlos III, Madrid, Spain.
Elena
E
Lorenzo
Department of Neurology, Mayo Clinic, Jacksonville, Florida, United States of America.
Audrey J
AJ
Strongosky
Department of Neurology, Mayo Clinic, Jacksonville, Florida, United States of America.
Jay A
JA
van Gerpen
Department of Neurology, Mayo Clinic, Jacksonville, Florida, United States of America.
Ryan J
RJ
Uitti
Department of Neurology, Mayo Clinic, Jacksonville, Florida, United States of America.
Zbigniew K
ZK
Wszolek
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, United States of America; Mayo Graduate School, Neurobiology of Disease, Mayo Clinic, Jacksonville, Florida, United States of America.
Owen A
OA
Ross
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D020329:Essential Tremor / Q000235:genetics*; D005091:Exons; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D049790:Nuclear Export Signals; D034802:RNA-Binding Protein EWS; D034702:RNA-Binding Protein FUS / Q000737:chemistry* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA
D002148:Calmodulin-Binding Proteins; C500986:EWSR1 protein, human; D049790:Nuclear Export Signals; D034802:RNA-Binding Protein EWS; D034702:RNA-Binding Protein FUS; D016601:RNA-Binding Proteins