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Abstract Details

Exome Sequencing Identifies FUS Mutations as a Cause of Essential Tremor
Movement Disorders
P05 - (-)
031
BACKGROUND: ET is a common neurodegenerative disorder that is characterized by a postural or motion tremor. Linkage studies on families have identified three ET-associated loci (ETM1, ETM2 , and ETM3). A common variation in dopamine D3 receptor within the ETM1 locus has been suggested to be a susceptibility factor for ET. However, this association has not been consistently replicated. More recently, common sequence variants in LINGO1 have been associated with ET,but the significance of these findings remains unclear as well.
DESIGN/METHODS: One ET-affected family, FET1, was chosen for study. During clinical assessment, ET was diagnosed as either definite, probable, or possible. The genomic DNA from four individuals with a definite ET diagnosis and an age of onset before 40 years and from a clinically unaffected married-in family member was captured with Agilent SureSelect all exome kits and sequenced with an Applied Biosystems SOLiD apparatus.
RESULTS: We identified a FUS p.Gln290 mutation as the cause of ET in this family. Further screening of 270 ET cases identified two additional rare missense FUS variants. Functional considerations suggest that the pathogenic effects of ET-specific FUS mutations are different from the effects observed when FUS is mutated in amyotrophic lateral sclerosis cases; we have shown that the ET FUS nonsense mutation is degraded by the nonsense-mediated-decay pathway, whereas amyotrophic lateral sclerosis FUS mutant transcripts are not.
CONCLUSIONS: We identified FUS c.868C>T (p.Gln290) as the pathogenic variant that causes ET in family FET1.
Authors/Disclosures
Nicolas Dupre, MD, FAAN (CHU de Quebec - U Laval)
PRESENTER 		Dr. Dupre has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Akcea Therapeutics Canada. The institution of Dr. Dupre has received research support from ARSACS Foundation. The institution of Dr. Dupre has received research support from CHUdeQuebec Foundation.
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Jean-Baptiste Riviere, MSc No disclosure on file
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Michel Panisset, MD No disclosure on file
Patrick Cossette, MD (CHUM) No disclosure on file
Genevieve Bernard, MD (Research Institute of the McGill University Health Centre) Dr. Bernard has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Calico. Dr. Bernard has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Orchard Therapeutics. Dr. Bernard has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for N/A. The institution of Dr. Bernard has received research support from Canadian Institutes of Health Research. The institution of Dr. Bernard has received research support from Montreal Children's Foundation. The institution of Dr. Bernard has received research support from Yaya Foundation for 4H Leukodystrophy. The institution of Dr. Bernard has received research support from Fondation Les Amis d'Elliot. The institution of Dr. Bernard has received research support from Ionis. Dr. Bernard has a non-compensated relationship as a Member of the Scientific Advisory Board with Pelizaeus-Merzbacher Foundation that is relevant to AAN interests or activities. Dr. Bernard has a non-compensated relationship as a Member of the Medical and Scientific Advisory Board with United Leukodystrophy Foundation that is relevant to AAN interests or activities. Dr. Bernard has a non-compensated relationship as a Chair of the Medical and Scientific Advisory Board with United Leukodystrophy Foundation that is relevant to AAN interests or activities. Dr. Bernard has a non-compensated relationship as a Member of the Scientific and Clinical advisory Council with Yaya Foundation that is relevant to AAN interests or activities.
Sylvain Chouinard, MD (CHUM-Notre-Dame) No disclosure on file
No disclosure on file
Guy A. Rouleau, MD, PhD, FAAN (Montreal Neurological Institute and Hospital) Dr. Rouleau has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NovoNordisk. Dr. Rouleau has received personal compensation in the range of $5,000-$9,999 for serving as an officer or member of the Board of Directors for AL-S Pharma.