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Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases
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نویسنده
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pierson t.m. ,adams d. ,bonn f. ,martinelli p. ,cherukuri p.f. ,teer j.k. ,hansen n.f. ,cruz p. ,mullikin j.c. ,blakesley r.w. ,golas g. ,kwan j. ,sandler a. ,fajardo k. ,markello t. ,tifft c. ,blackstone c. ,rugarli e.i. ,langer t. ,gahl w.a. ,toro c.
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منبع
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plos genetics - 2011 - دوره : 7 - شماره : 10
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چکیده
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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.
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آدرس
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nih undiagnosed diseases program,national institutes of health office of rare diseases research,national human genome research institute,bethesda,md,united states,neurogenetics branch,national institute of neurological disorders and stroke,national institutes of health,bethesda,md, United States, nih undiagnosed diseases program,national institutes of health office of rare diseases research,national human genome research institute,bethesda,md,united states,office of the clinical director,national human genome research institute,national institutes of health,bethesda,md, United States, institute for genetics,university of cologne,cologne, Germany, biocenter,university of cologne,cologne, Germany, genome technology branch,national human genome research institute,national institutes of health,bethesda,md, United States, genetic disease research branch,national human genome research institute,national institutes of health,bethesda,md, United States, genome technology branch,national human genome research institute,national institutes of health,bethesda,md, United States, genome technology branch,national human genome research institute,national institutes of health,bethesda,md, United States, genome technology branch,national human genome research institute,national institutes of health,bethesda,md,united states,nih intramural sequencing center,national human genome research institute,national institutes of health,bethesda,md, United States, genome technology branch,national human genome research institute,national institutes of health,bethesda,md, United States, nih undiagnosed diseases program,national institutes of health office of rare diseases research,national human genome research institute,bethesda,md,united states,office of the clinical director,national human genome research institute,national institutes of health,bethesda,md, United States, emg section,national institute of neurological disorders and stroke,national institutes of health,bethesda,md, United States, division of surgery,children's national medical center,washington,d.c., United States, nih undiagnosed diseases program,national institutes of health office of rare diseases research,national human genome research institute,bethesda,md, United States, nih undiagnosed diseases program,national institutes of health office of rare diseases research,national human genome research institute,bethesda,md,united states,office of the clinical director,national human genome research institute,national institutes of health,bethesda,md, United States, nih undiagnosed diseases program,national institutes of health office of rare diseases research,national human genome research institute,bethesda,md,united states,office of the clinical director,national human genome research institute,national institutes of health,bethesda,md, United States, neurogenetics branch,national institute of neurological disorders and stroke,national institutes of health,bethesda,md, United States, biocenter,university of cologne,cologne, Germany, institute for genetics,center for molecular medicine (cmmc),cecad,university of cologne,cologne,germany,max-planck-institute for biology of aging,cologne, Germany, nih undiagnosed diseases program,national institutes of health office of rare diseases research,national human genome research institute,bethesda,md,united states,office of the clinical director,national human genome research institute,national institutes of health,bethesda,md, United States, nih undiagnosed diseases program,national institutes of health office of rare diseases research,national human genome research institute,bethesda,md, United States
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Authors
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