Clonal expansion of secondary mitochondrial DNA deletions associated with spinocerebellar ataxia type 28.
JAMA Neurol
; 72(1): 106-11, 2015 Jan.
Article
en En
| MEDLINE
| ID: mdl-25420100
ABSTRACT
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 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 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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
ADN Mitocondrial
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Degeneraciones Espinocerebelosas
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Enfermedades Mitocondriales
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Proteasas ATP-Dependientes
Tipo de estudio:
Observational_studies
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Risk_factors_studies
Límite:
Aged
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Animals
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Female
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Humans
Idioma:
En
Revista:
JAMA Neurol
Año:
2015
Tipo del documento:
Article