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

Valerio Carelli, Simone Schimpf, Nico Fuhrmann, Maria Lucia Valentino, Claudia Zanna, Luisa Iommarini, Monika Papke, Simone Schaich, Sabine Tippmann, Britta Baumann, Piero Barboni, Lora Longanesi, Michela Rugolo, Anna Ghelli, Marcel V. Alavi, Richard J. Youle, Laura Bucchi, Rosanna Carroccia, Maria Pia Giannoccaro, Caterina TononRaffaele Lodi, Giovanna Cenacchi, Pasquale Montagna, Rocco Liguori, Bernd Wissinger

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article numberddr071
Pages (from-to)1893-1905
Number of pages13
JournalHuman Molecular Genetics
Issue number10
Publication statusPublished - May 2011

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology


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