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Clonal Expansion of Secondary Mitochondrial DNA Deletions Associated With Spinocerebellar Ataxia Type 28

Lookup NU author(s): Professor Grainne Gorman, Dr Gerald Pfeffer, Dr Helen GriffinORCiD, Dr Marzena Kurzawa-Akanbi, Jessica Gabriel, Dr Kamil Sitarz, Dr Angela Pyle, Professor Bobby McFarlandORCiD, Emeritus Professor Doug Turnbull, Professor Rita HorvathORCiD, Professor Patrick Chinnery, Professor Robert Taylor


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IMPORTANCE 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.OBSERVATIONS Whole-exome sequencing identified a novel, heterozygous p.(Gly671Trp) mutation in the AFG3L2 gene encoding anmt 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 AND RELEVANCE 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.

Publication metadata

Author(s): Gorman GS, Pfeffer G, Griffin H, Blakely EL, Kurzawa-Akanbi M, Gabriel J, Sitarz K, Roberts M, Schoser B, Pyle A, Schaefer AM, McFarland R, Turnbull DM, Horvath R, Chinnery PF, Taylor RW

Publication type: Article

Publication status: Published

Journal: JAMA Neurology

Year: 2015

Volume: 72

Issue: 1

Pages: 106-111

Print publication date: 01/01/2015

Online publication date: 24/11/2014

Acceptance date: 22/05/2014

ISSN (print): 2168-6149

ISSN (electronic): 2168-6157

Publisher: American Medical Association


DOI: 10.1001/jamaneurol.2014.1753


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Funder referenceFunder name
Canadian Institutes of Health Research
National Institute for Health Research (NIHR) Biomedical Research Centre funding scheme based at Newcastle upon Tyne Hospitals NHS Foundation Trust
Newcastle University
NIHR Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust
UK National Health Service (NHS) Specialised Service for Rare Mitochondrial Diseases of Adults and Children, Newcastle
UK NHS Highly Specialised Rare Mitochondrial Disorders of Adults and Children Service
096919Z/11/ZWellcome Trust Centre for Mitochondrial Research
G0601943Medical Research Council (UK) Centre for Translational Muscle Disease Research
G0800674Medical Research Council (UK) Mitochondrial Disease Patient Cohort