Clonal expansion of secondary mitochondrial DNA deletions associated with spinocerebellar ataxia type 28
| Autor: | Jessica Gabriel, Douglass M. Turnbull, Marzena Kurzawa-Akanbi, Grainne S. Gorman, Andrew M. Schaefer, Benedikt Schoser, Angela Pyle, Rita Horvath, Emma L. Blakely, Patrick F. Chinnery, Robert McFarland, Robert W. Taylor, Gerald Pfeffer, Mark Roberts, Helen Griffin, Kamil S. Sitarz |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Mitochondrial DNA
Ophthalmoplegia Chronic Progressive External Ataxia Mitochondrial Diseases Somatic cell Biology medicine.disease_cause DNA Mitochondrial Evolution Molecular ATP-Dependent Proteases medicine Animals Humans Spinocerebellar Ataxias Muscle Skeletal Exome sequencing Aged Spinocerebellar Degenerations Genetics Mutation Fibroblasts medicine.disease Phenotype Blot Case-Control Studies Spinocerebellar ataxia ATPases Associated with Diverse Cellular Activities Female Neurology (clinical) medicine.symptom Genome-Wide Association Study |
| Zdroj: | JAMA neurology. 72(1) |
| ISSN: | 2168-6157 |
| Popis: | 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 theAFG3L2gene 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)AFG3L2mutation. Analysis of patient fibroblasts revealed mt fragmentation and decreasedAFG3L2transcript expression. Western blotting of patient fibroblast and muscle showed decreased AFG3L2 protein levels. Conclusions and Relevance Our observations suggest thatAFG3L2mutations are another important cause, albeit rare, of a late-onset ataxic PEO phenotype due to a disturbance of mtDNA maintenance. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|