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 AFG3L2Y616C gene product is a hypomorphic variant that exhibited oligomerization defects in yeast as well as in patient fibroblasts. Specifically, the formation of AFG3L2Y616C 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.

Loss of Drosophila i-AAA protease, dYME1L, causes abnormal mitochondria and apoptotic degeneration

“…7 Mutations in the mitochondrial m-AAA proteases are responsible for neurodegenerative disorders including hereditary spastic paraplegia (HSP), spinocerebellar ataxia (SCA28) and spastic ataxia neuropathy syndrome. [8][9][10] However, the degenerative mechanisms remain elusive, 11 and the presence of multiple mitochondrial m-AAA proteases with redundant functions in eukaryotes complicates their analysis in animal models. By contrast, only one mitochondrial i-AAA protease has been identified in eukaryotic genomes.…”

Ataxia

“…2,27,28 Whole exome sequencing and whole genome sequencing are especially useful in detecting genetic mutations known to cause specific diseases. However, these technologies have technical limitations in diagnosing a repeat expansion disorder.…”

Next-generation sequencing: impact of exome sequencing in characterizing Mendelian disorders

“…However, if we study a family with four affected individuals or two or three families, each with at least two affected ones, employing the usual filtering could possibly define a causal gene. [41][42][43][44][45] According to an assumption by Robinson et al, 46 when the same gene is considered as a causality in multi sporadic cases, 5% of the target genes (about 20 000) show rare probable casual variants in all affected individuals, and after sequencing one individual and a usual filtering, nearly 1000 genes would remain as candidate genes. If a second individual is sequenced, only 50 genes (5% of 1000) with variants in both individuals will remain.…”