A clinically complex form of dominant optic atrophy (OPA8) maps on chromosome 16

Abstract

Dominant optic atrophy (DOA) is genetically heterogeneous and pathogenic mutations have been identified in the OPA1 and OPA3 genes, both encoding for mitochondrial proteins. We characterized clinical and laboratory features in a large OPA1-negative family with complicated DOA. Search for mitochondrial dysfunction was performed by studying muscle biopsies, fibroblasts, platelets and magnetic resonance (MR) spectroscopy. Genetic investigations included mitochondrial DNA (mtDNA) analysis, linkage analysis, copy number variation (CNV) analysis and candidate gene screening. Optic neuropathy was undistinguishable from that in OPA1-DOA and frequently associated with late-onset sensorineural hearing loss, increases of central conduction times at somato-sensory evoked potentials and various cardiac abnormalities. Serum lactic acid after exercise, platelet respiratory complex activities, adenosine triphosphate (ATP) content in fibroblasts and muscle phosphorus MR spectroscopy all failed to reveal a mitochondrial dysfunction. However, muscle biopsies and their mtDNA analysis showed increased mitochondrial biogenesis. Furthermore, patient's fibroblasts grown in the galactose medium were unable to increase ATP content compared with controls, and exhibited abnormally high rate of fusion activity. Genome-wide linkage revealed a locus on chromosome 16q21-q22 with a maximum two-point LOD score of 8.84 for the marker D16S752 and a non-recombinant interval of ∼ 6.96 cM. Genomic screening of 45 genes in this interval including several likely candidate genes (CALB2, CYB5B, TK2, DHODH, PLEKHG4) revealed no mutation. Moreover, we excluded the presence of CNVs using array-based comparative genome hybridization. The identification of a new OPA locus (OPA8) in this pedigree demonstrates further genetic heterogeneity in DOA, and our results indicate that the pathogenesis may still involve mitochondria.

Identification of copy number variation in the gene for autosomal dominant optic atrophy, OPA1, in a Chinese pedigree

“…In the study of Almind et al (2011), the researchers aimed to identify CNVs in the OPA1 gene in Danish patients with ADOA, and they found that ten families (10% of all patients) had OPA1 deletions. However, in contrast to this report, in an Italian pedigree with complicated ADOA, CNVs were not found (Carelli et al, 2011). The role of CNV in ADOA, therefore, is still unknown.…”

“…In accordance with these findings, we identified a deletion of exons 1-9 in the OPA1 gene, but did not find any point mutations in OPA1. In contrast, in an Italian pedigree with ADOA, a new locus (OPA8) on chromosome 16q21-q22 was identified, but CNVs were not found (Carelli et al, 2011). The different results in the pedigrees with ADOA might be a consequence of the differences in the human species (genetic background) or the use of different methodologies to detect CNVs.…”

“…Genetic analysis of ADOA families identified two loci on chromosome 18q12.2-q12.3 (OPA4) and chromosome 22q (OPA5) (Kerrison et al, 1999;Barbet et al, 2005). Recently, Carelli et al (2011) identified a new locus (OPA8) on chromosome 16q21-q22 in an Italian pedigree with complicated ADOA. Additional loci and genes, such as OPA2, -6, and -7, are described in relation to X-linked or recessive optic atrophy (Katz et al, 2006;Desir et al, 2012).…”

Compound heterozygosity for severe and hypomorphicNDUFS2mutations cause non-syndromic LHON-like optic neuropathy

“…Hitherto, the vast majority of non-syndromic optic neuropathies have been ascribed to maternally inherited mutations in mitochondrial DNA-encoded respiratory chain enzyme genes (MTND1, OMIM#516000; MTND4, OMIM#516003; MTND5, OMIM#516005; MTND6, OMIM#516006; MTCYB, OMIM#516020) and dominant mutations in the nuclear-encoded mitochondrial dynamic gene OPA1 , (OMIM#605290) or other nuclear-encoded genes of known or unknown mitochondrial function (SPG7 , OMIM#602783;27 OPA8 , OMIM#616648) 28. In contrast, autosomal recessive non-syndromic optic neuropathies are uncommon.…”

Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy

“…On the other hand, optic neuropathy has been ascribed to mutations in mitochondrial fusion/fission dynamic genes, ( OPA1 , MIM6052908; MFN2 , MIM6085078; DNM1 L, MIM6038508), nuclear or mitochondrial DNA-encoded respiratory chain enzyme genes ( MTND1 , MIM516000; MTND4 , MIM516003; MTND5 , MIM516005; MTND6 , MIM516006; MTCYB , MIM5160209) or other nuclear genes of known or unknown mitochondrial function ( TIMM8A , MIM30035610; TMEM126A , MIM61298811; OPA3 , MIM60658012; OPA8 13; SPG7 , MIM602783,14 C19orf12 , MIM61429815; C12orf65 MIM 61354116; TSFM , MIM60472317) . While isocitrate dehydrogenase ( IDH3 ) mutation has been reported to cause isolated retinitis pigmentosa,2 TCA enzymes have never been hitherto shown to cause isolated optic neuropathy.…”