Abstract Details

Title A VAMP1 Mutation Causes Chromosome 12p13 Hereditary Spastic Ataxia in Newfoundland Families

Topic Movement Disorders

Presentation(s) S43 - (-)

Poster/Presentation
Number 002

Background Spastic ataxia 1 is a autosomal dominant form of hereditary spastic ataxia characterized by lower-limb spasticity and ataxia in the form of head jerks, ocular movement abnormalities, dysphagia, dysarthria and gait disturbance. We previously mapped SPAX1 in three Newfoundland families to chromosome 12p13.

Objective

Design/Methods A mutation-screening panel including two affected individuals from two different families and an unaffected control was established. All coding exons and flanking intronic regions of the 53 genes and predicted genes located in the 1.9 Mb disease haplotype were amplified by polymerase-chain reaction and sequenced. The variants were validated by segregation analysis, by screening 169 Newfoundland population controls and by bioinformatic analysis. VAMP1 minigenes were also developped to study the mutation's effect on splicing.

Results A heterozygote mutation at the position chr12:g. 6,574,054 T>G in VAMP1 was identified. This variant segregated in the three families and was also identified in three HSA probands from Ontario (Canada). The VAMP1 gene has three isoforms and in silico programs suggest that the variant leads to a damaging p.Ser114Arg mutation in isoform VAMP1D whereas the c.340 + 2 T>G variant would disrupt mRNA splicing by changing the GT splicing donor site in isoform VAMP1A and VAMP1B. The effect on splicing was confirmed in a VAMP1 minigene system and it is hypothesized that the mutation leads to the loss of VAMP1A.

Conclusions We identified the mutated VAMP1 gene, which encodes a critical protein for synaptic exocytosis as the cause of SPAX1 . Given the variable phenotype seen in the affected individuals examined here, we believe VAMP1 should be tested for mutations in patients with either ataxia or spastic paraplegia.

Authors/Disclosures
Inge Meijer, MD, PhD (CHU Sainte Justine) PRESENTER	Dr. Meijer has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Allergan. Dr. Meijer has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Mark G. Stefanelli, MD (Health Sciences Centre/Div of Neuro)	No disclosure on file
	No disclosure on file
	No disclosure on file
William Pryse-Phillips, MD	No disclosure on file
Mercè Boada Rovira, MD, PhD (Fundació ACE. Institut Català de Neurociènces Aplicades)	Dr. Boada Rovira has received personal compensation for serving as an employee of FUNDACIO ACE. ICNA. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GRIFOLS. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ARACLON BIOTECH. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ROCHE. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BIOGEN. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lilly. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MERCK. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ZAMBON. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for GRIFOLS. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ARACLON BIOTECH. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ROCHE. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BIOGEN. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for LILLY. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for MERCK. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ZAMBON. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NOVO NORDISK. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BIOIBERICA. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for SERVIER. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EISAI. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for SCHWABE PHARMA. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ROCHE. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BIOGEN. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for GRIFOLS. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for NUTRICIA. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for ARACLON BIOTECH. The institution of Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for SERVIER. Dr. Boada Rovira has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for ZAMBON.
Mandar S. Jog, MD, FAAN (University of Western Ontario)	Dr. Jog has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Merz. Dr. Jog has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Abbvie. Dr. Jog has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Ipsen. Dr. Jog has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Abbvie. Dr. Jog has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Ipsen. Dr. Jog has stock in MDDT .
Kym Boycott	No disclosure on file
David A. Grimes, MD	No disclosure on file
	No disclosure on file
Richard N. Leckey, MD (Maritime Neurology)	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.

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