Abstract
Dominant optic neuropathies causing fiber loss in the optic nerve are among the most frequent inherited mitochondrial diseases. In most genetically resolved cases, the disease is associated to a mutation in OPA1, which encodes an inner mitochondrial dynamin involved in network fusion, cristae structure and mitochondrial genome maintenance. OPA1 cleavage is regulated by two m-AAA proteases, SPG7 and AFG3L2, which are, respectively involved in Spastic Paraplegia 7 and Spino-Cerebellar Ataxia 28. Here, we identified a novel mutation c.1402C>T in AFG3L2, modifying the arginine 468 in cysteine in an evolutionary highly conserved arginine-finger motif, in a family with optic atrophy and mild intellectual disability. Ophthalmic examinations disclosed a loss of retinal nerve fibers on the temporal and nasal sides of the optic disk and a red–green dyschromatopsia. Thus, our results suggest that neuro-ophthalmological symptom as optic atrophy might be associated with AFG3L2 mutations, and should prompt the screening of this gene in patients with isolated and syndromic inherited optic neuropathies.
Highlights
Dominant optic atrophy (DOA) is a neurodegenerative disease that primarily targets the retinal ganglion cell (RGC), representing an important cause of early onset blindness
AFG3L2 down-regulation affects respiratory capacity and calcium uptake, and induces mitochondrial network fragmentation (Maltecca et al, 2012), a cellular phenotype that we found in cell lines with altered OPA1 expression is caused by OPA1 haplo-insufficiency or eventually by a dominant negative process (Olichon et al, 2007)
It is possible that asymptomatic optic atrophy exists in SCA28 and SPAX5 patients since decreased visual acuity can be absent in moderate forms of optic atrophy, suggesting that future patients with AFG3L2 mutations should have systematic fundus and optical coherence tomography (OCT) examinations
Summary
Dominant optic atrophy (DOA) is a neurodegenerative disease that primarily targets the retinal ganglion cell (RGC), representing an important cause of early onset blindness. 30 deleterious SNPs predicted by SIFT, PolyPhen-2, and Mutation Taster softwares were retained (see Supplementary Table S1) These variants were filtered for heterozygous mutations in gene encoding mitochondrial protein (MitoCarta), as to date all DOA genes are involved in mitochondrial physiology. In silico prediction of the p.Arg468Cys pathogenicity by Polyphen, SIFT, Mutation taster, imutant, Pmut, MetaSVM, MetaLR, FathMM, and PhD-SNP programs gave the highest scores, supporting the pathogenicity of this mutation This 48-year-old male complained of visual difficulties since 12 years of age including decrease in visual acuity, photophobia, and color vision impairment with very slow progression of visual loss. He otherwise had normal development without neuromuscular or other sensory involvement, but he had mild intellectual disability. The other family members were not compliant with clinical and genetic analysis
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