Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases.

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.

• Authors: Tyler Mark Pierson, David Adams, Florian Bonn, Paola Martinelli, Praveen F Cherukuri, Jamie K Teer, Nancy F Hansen, Pedro Cruz, James C Mullikin For The Nisc Comparative Sequencing Program, Robert W Blakesley, Gretchen Golas, Justin Kwan, Anthony Sandler, Karin Fuentes Fajardo, Thomas Markello, Cynthia Tifft, Craig Blackstone, Elena I Rugarli, Thomas Langer, William A Gahl, Camilo Toro
• Journal: PLoS genetics (PLoS Genet) Vol. 7 Issue 10 Pg. e1002325 (Oct 2011) ISSN: 1553-7404 [Electronic] United States
• PMID: 22022284 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• ATP-Dependent Proteases
• AFG3L2 protein, human
• Metalloendopeptidases
• SPG7 protein, human
• m-AAA proteases
• ATPases Associated with Diverse Cellular Activities

Topics

• ATP-Dependent Proteases (genetics)
• ATPases Associated with Diverse Cellular Activities
• Adolescent
• Amino Acid Sequence
• Animals
• Brain (abnormalities, pathology)
• Child
• Diagnosis, Differential
• Exome (genetics)
• Genotype
• HeLa Cells
• Homozygote
• Humans
• Male
• Metalloendopeptidases (genetics, metabolism)
• Mice
• Mitochondria (enzymology)
• Molecular Sequence Data
• Mutation, Missense
• Paraplegia
• Protein Folding
• Siblings
• Spastic Paraplegia, Hereditary (genetics, pathology)
• Spinocerebellar Ataxias (congenital)
• Spinocerebellar Degenerations (genetics, pathology)
• Yeasts (genetics)