title: Clonal expansion of secondary mitochondrial DNA deletions associated with spinocerebellar ataxia type 28.
abstract: OBJECTIVE
  Progressive external ophthalmoplegia (PEO) is a common feature in adults with mitochondrial (mt) DNA maintenance disorders associated with somatic mtDNA deletions in muscle, yet the causal genetic defect in many patients remains undetermined.
  
  
  METHODS
  Whole-exome sequencing identified a novel, heterozygous p.(Gly671Trp) mutation in the AFG3L2 gene encoding an mt protease--previously associated with dominant spinocerebellar ataxia type 28 disease--in a patient with indolent ataxia and PEO. Targeted analysis of a larger, genetically undetermined cohort of patients with PEO with suspected mtDNA maintenance abnormalities identified a second unrelated patient with a similar phenotype and a novel, heterozygous p.(Tyr689His) AFG3L2 mutation. Analysis of patient fibroblasts revealed mt fragmentation and decreased AFG3L2 transcript expression. Western blotting of patient fibroblast and muscle showed decreased AFG3L2 protein levels.
  
  
  CONCLUSIONS
  Our observations suggest that AFG3L2 mutations are another important cause, albeit rare, of a late-onset ataxic PEO phenotype due to a disturbance of mtDNA maintenance.
authors.affiliation: Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, England2Institute for Ageing and Health, National Institute for Health Research Biomedical Research Centre for Ageing, Newcastle University, Newcastle upon Tyne, Englan.
authors.forename: Gráinne S
authors.initials: GS
authors.lastname: Gorman
authors.affiliation: Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, England3Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Gerald
authors.initials: G
authors.lastname: Pfeffer
authors.affiliation: Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, England3Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Helen
authors.initials: H
authors.lastname: Griffin
authors.affiliation: Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, England2Institute for Ageing and Health, National Institute for Health Research Biomedical Research Centre for Ageing, Newcastle University, Newcastle upon Tyne, Englan.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Blakely
authors.affiliation: Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, England3Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Marzena
authors.initials: M
authors.lastname: Kurzawa-Akanbi
authors.affiliation: Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Jessica
authors.initials: J
authors.lastname: Gabriel
authors.affiliation: Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, England3Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Kamil
authors.initials: K
authors.lastname: Sitarz
authors.affiliation: Department of Neurology, Hope Hospital, Salford, England.
authors.forename: Mark
authors.initials: M
authors.lastname: Roberts
authors.affiliation: Friedrich-Baur Institut, Department of Neurology, Ludwig-Maximilians University, München, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Schoser
authors.affiliation: Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, England3Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Angela
authors.initials: A
authors.lastname: Pyle
authors.affiliation: Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Schaefer
authors.affiliation: Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, England2Institute for Ageing and Health, National Institute for Health Research Biomedical Research Centre for Ageing, Newcastle University, Newcastle upon Tyne, Englan.
authors.forename: Robert
authors.initials: R
authors.lastname: McFarland
authors.affiliation: Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, England2Institute for Ageing and Health, National Institute for Health Research Biomedical Research Centre for Ageing, Newcastle University, Newcastle upon Tyne, Englan.
authors.forename: Douglass M
authors.initials: DM
authors.lastname: Turnbull
authors.affiliation: Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, England3Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.affiliation: Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, England3Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, England.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.affiliation: Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, England2Institute for Ageing and Health, National Institute for Health Research Biomedical Research Centre for Ageing, Newcastle University, Newcastle upon Tyne, Englan.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Taylor
mesh_terms: D049069:ATP-Dependent Proteases / Q000235:genetics*; D000074183:ATPases Associated with Diverse Cellular Activities; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D004272:DNA, Mitochondrial / Q000235:genetics*; D019143:Evolution, Molecular; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D055106:Genome-Wide Association Study; D006801:Humans; D028361:Mitochondrial Diseases / Q000235:genetics*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D017246:Ophthalmoplegia, Chronic Progressive External / Q000235:genetics; D020754:Spinocerebellar Ataxias / Q000151:congenital; D013132:Spinocerebellar Degenerations / Q000235:genetics* / Q000473:pathology
chemical_list: D004272:DNA, Mitochondrial; D049069:ATP-Dependent Proteases; C120699:AFG3L2 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities