title: 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.
authors.affiliation: Department of Neurological Sciences, University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy. valerio.carelli@unibo.it
authors.forename: Valerio
authors.initials: V
authors.lastname: Carelli
authors.forename: Simone
authors.initials: S
authors.lastname: Schimpf
authors.forename: Nico
authors.initials: N
authors.lastname: Fuhrmann
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Valentino
authors.forename: Claudia
authors.initials: C
authors.lastname: Zanna
authors.forename: Luisa
authors.initials: L
authors.lastname: Iommarini
authors.forename: Monika
authors.initials: M
authors.lastname: Papke
authors.forename: Simone
authors.initials: S
authors.lastname: Schaich
authors.forename: Sabine
authors.initials: S
authors.lastname: Tippmann
authors.forename: Britta
authors.initials: B
authors.lastname: Baumann
authors.forename: Piero
authors.initials: P
authors.lastname: Barboni
authors.forename: Lora
authors.initials: L
authors.lastname: Longanesi
authors.forename: Michela
authors.initials: M
authors.lastname: Rugolo
authors.forename: Anna
authors.initials: A
authors.lastname: Ghelli
authors.forename: Marcel V
authors.initials: MV
authors.lastname: Alavi
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Youle
authors.forename: Laura
authors.initials: L
authors.lastname: Bucchi
authors.forename: Rosanna
authors.initials: R
authors.lastname: Carroccia
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Giannoccaro
authors.forename: Caterina
authors.initials: C
authors.lastname: Tonon
authors.forename: Raffaele
authors.initials: R
authors.lastname: Lodi
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cenacchi
authors.forename: Pasquale
authors.initials: P
authors.lastname: Montagna
authors.forename: Rocco
authors.initials: R
authors.lastname: Liguori
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic / Q000235:genetics; D012171:Retinal Vessels / Q000473:pathology; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial