Abstract Details

Title A Novel Autosomal Dominant Dystonia and Spastic Paraplegia Caused by a Mutation in ATP5G3, a Gene That Encodes for Subunit C of Mitochondrial ATP Synthase

Topic Movement Disorders

Presentation(s) S53 - (-)

Poster/Presentation
Number 002

Objective

Background We previously characterized the phenotype of this disease which has highly variable onset between the first year and fifth decade. Clinically it presents with progressive, deep brain stimulation-responsive idiopathic generalized dystonia in childhood and/or spastic paraplegia in adulthood. Linkage to chromosome 2q24-2q31 was identified, in a region in which no prior inherited dystonias or spastic paraplegias had been identified.

Design/Methods Forty family members were seen and examined of whom 18 were affected. Exome sequencing was performed on two distantly-related family members. The resulting analysis was constrained to the genetic locus on chromosome 2q. Confirmatory Sanger-based sequencing was performed on the remainder of the affected and unaffected family members.

Results A single, novel heterozygous mutation (p. 102N>K) in ATP5G3 was identified in a highly conserved region of the c subunit of mitochondrial complex V ATP synthase. This mutation segregated with disease in the family. ATP synthase catalyzes ATP synthesis during oxidative phosphorylation. The c subunits of this complex form the trans-membrane proton pore structure. In E. coli, mutation of the corresponding amino acid causes uncoupling of oxidative phosphorylation, suggesting a possible novel mechanism for this disease.

Conclusions A specific mutation and amino acid substitution in complex c of mitochondrial ATP synthase causes progressive generalized dystonia and spastic paraplegia. No human diseases resulting from mutations in ATP5G3 have previously been described. Studies in progress to determine the pathophysiology may identify important mechanisms for neurological dysfunction in this and other progressive neurological diseases.

Authors/Disclosures
Donald Gilbert, MD, FAAN (Cincinnati Children's Hospital Med. Ctr.) PRESENTER	Dr. Gilbert has received personal compensation in the range of $500-$4,999 for serving as a Consultant for PTC Therapeutics. Dr. Gilbert has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Illumina. Dr. Gilbert has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Emalex Biosciences. The institution of Dr. Gilbert has received research support from NIMH. The institution of Dr. Gilbert has received research support from Emalex Biosciences. The institution of Dr. Gilbert has received research support from PTC Therapeutics. The institution of Dr. Gilbert has received research support from Department of Defense. The institution of Dr. Gilbert has received research support from Quince Therapeutics. Dr. Gilbert has received publishing royalties from a publication relating to health care. Dr. Gilbert has received publishing royalties from a publication relating to health care. Dr. Gilbert has received personal compensation in the range of $500-$4,999 for serving as a Medical Second Opinion Expert with Teldoc/Advanced Medical. Dr. Gilbert has received personal compensation in the range of $10,000-$49,999 for serving as a Medical Expert with Department of Health and Human Services/Vaccine Injury Compensation Program.
	No disclosure on file
Carlo Colosimo, MD (Universita La Sapienza)	No disclosure on file
	No disclosure on file
Derek Neilson	Derek Neilson has nothing to disclose.

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