Pierson, Tyler Mark, Adams, David, Bonn, Florian, Martinelli, Paola, Cherukuri, Praveen F., Teer, Jamie K., Hansen, Nancy F., Cruz, Pedro, Mullikin, James C., Blakesley, Robert W., Golas, Gretchen, Kwan, Justin, Sandler, Anthony ORCID: 0000-0001-9440-2964, Fajardo, Karin Fuentes, Markello, Thomas, Tifft, Cynthia, Blackstone, Craig, Rugarli, Elena I., Langer, Thomas ORCID: 0000-0003-1250-1462, Gahl, William A. and Toro, Camilo (2011). Whole-Exome Sequencing Identifies Homozygous AFG3L2 Mutations in a Spastic Ataxia-Neuropathy Syndrome Linked to Mitochondrial m-AAA Proteases. PLoS Genet., 7 (10). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1553-7390

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Pierson, Tyler MarkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Adams, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bonn, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Martinelli, PaolaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cherukuri, Praveen F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Teer, Jamie K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hansen, Nancy F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cruz, PedroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mullikin, James C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blakesley, Robert W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Golas, GretchenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kwan, JustinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sandler, AnthonyUNSPECIFIEDorcid.org/0000-0001-9440-2964UNSPECIFIED
Fajardo, Karin FuentesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Markello, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tifft, CynthiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blackstone, CraigUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rugarli, Elena I.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Langer, ThomasUNSPECIFIEDorcid.org/0000-0003-1250-1462UNSPECIFIED
Gahl, William A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toro, CamiloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-488584
DOI: 10.1371/journal.pgen.1002325
Journal or Publication Title: PLoS Genet.
Volume: 7
Number: 10
Date: 2011
Publisher: PUBLIC LIBRARY SCIENCE
Place of Publication: SAN FRANCISCO
ISSN: 1553-7390
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DIMETHYLGLYCINE DEHYDROGENASE; INBORN ERROR; PARAPLEGIA; DEGENERATION; SCA28; GENE; METALLOPROTEASE; IMPAIRMENT; DEFICIENCY; METABOLISMMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/48858

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