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Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases.
Pierson, Tyler Mark; Adams, David; Bonn, Florian; Martinelli, Paola; Cherukuri, Praveen F; Teer, Jamie K; Hansen, Nancy F; Cruz, Pedro; Mullikin For The Nisc Comparative Sequencing Program, James C; Blakesley, Robert W; Golas, Gretchen; Kwan, Justin; Sandler, Anthony; Fuentes Fajardo, Karin; Markello, Thomas; Tifft, Cynthia; Blackstone, Craig; Rugarli, Elena I; Langer, Thomas; Gahl, William A; Toro, Camilo.
Afiliação
  • Pierson TM; NIH Undiagnosed Diseases Program, National Institutes of Health Office of Rare Diseases Research and National Human Genome Research Institute, Bethesda, Maryland, United States of America. piersonty@ninds.nih.gov
PLoS Genet ; 7(10): e1002325, 2011 Oct.
Article em En | MEDLINE | ID: mdl-22022284
ABSTRACT
We report an early onset spastic ataxia-neuropathy syndrome in two brothers of a consanguineous family characterized clinically by lower extremity spasticity, peripheral neuropathy, ptosis, oculomotor apraxia, dystonia, cerebellar atrophy, and progressive myoclonic epilepsy. Whole-exome sequencing identified a homozygous missense mutation (c.1847G>A; p.Y616C) in AFG3L2, encoding a subunit of an m-AAA protease. m-AAA proteases reside in the mitochondrial inner membrane and are responsible for removal of damaged or misfolded proteins and proteolytic activation of essential mitochondrial proteins. AFG3L2 forms either a homo-oligomeric isoenzyme or a hetero-oligomeric complex with paraplegin, a homologous protein mutated in hereditary spastic paraplegia type 7 (SPG7). Heterozygous loss-of-function mutations in AFG3L2 cause autosomal-dominant spinocerebellar ataxia type 28 (SCA28), a disorder whose phenotype is strikingly different from that of our patients. As defined in yeast complementation assays, the AFG3L2(Y616C) gene product is a hypomorphic variant that exhibited oligomerization defects in yeast as well as in patient fibroblasts. Specifically, the formation of AFG3L2(Y616C) complexes was impaired, both with itself and to a greater extent with paraplegin. This produced an early-onset clinical syndrome that combines the severe phenotypes of SPG7 and SCA28, in additional to other "mitochondrial" features such as oculomotor apraxia, extrapyramidal dysfunction, and myoclonic epilepsy. These findings expand the phenotype associated with AFG3L2 mutations and suggest that AFG3L2-related disease should be considered in the differential diagnosis of spastic ataxias.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Encéfalo / Metaloendopeptidases / Paraplegia Espástica Hereditária / Degenerações Espinocerebelares / Proteases Dependentes de ATP / Mitocôndrias Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Adolescent / Animals / Child / Humans / Male Idioma: En Revista: PLoS Genet Assunto da revista: GENETICA Ano de publicação: 2011 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Encéfalo / Metaloendopeptidases / Paraplegia Espástica Hereditária / Degenerações Espinocerebelares / Proteases Dependentes de ATP / Mitocôndrias Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Adolescent / Animals / Child / Humans / Male Idioma: En Revista: PLoS Genet Assunto da revista: GENETICA Ano de publicação: 2011 Tipo de documento: Article País de afiliação: Estados Unidos