title: Structural model of the OPA1 GTPase domain may explain the molecular consequences of a novel mutation in a family with autosomal dominant optic atrophy.
abstract: Autosomal dominant optic atrophy (ADOA) is the most frequent hereditary optic neuropathy. Three loci have been reported for ADOA: a major locus, harboring all identified mutations to date, maps to 3q28 (OPA1), a second locus is linked to 18q12.2-q12.3 (OPA4) and a third locus on 22q12.1-q13.1 (OPA5) has been reported recently. We describe a six-generation Iranian family in which optic atrophy runs as an autosomal dominant trait with an age of onset at 14-15years. We performed linkage analysis with markers mapping to 3q28 and 18q12.2-q12.3 and found linkage to 3q28. Subsequent sequencing of OPA1 identified a novel heterozygous missense mutation (c.1313A>G) replacing aspartic acid by glycine (p.D438G) in the GTPase domain of OPA1. Interestingly, another missense mutation at the same position (c.1313A>T, D438V) has been reported before in two unrelated German families, indicating a possible mutation hot spot. Further evidence supporting the importance of D438 is its conservation from human to acoelomata. OPA1 is believed to be the human orthologue of yeast MGM1, a dynamin-related protein required for the integrity of mitochondrial DNA. Homology modeling of the OPA1 GTPase domain revealed extensive structural similarity to the Dictyostelium dynamin A GTPase domain and showed that D438 may interact with residues of the G1 and the G4 motifs, which are crucial in coordinating GTP. Based on this analysis, we propose a mechanism which explains the gradual decline of vision in ADOA patients with OPA1 mutations at position 438.
authors.forename: Sharareh
authors.initials: S
authors.lastname: Dadgar
authors.forename: Olivier
authors.initials: O
authors.lastname: Hagens
authors.forename: Seyed Razi
authors.initials: SR
authors.lastname: Dadgar
authors.forename: Ehsan Nobakht
authors.initials: EN
authors.lastname: Haghighi
authors.forename: Simone
authors.initials: S
authors.lastname: Schimpf
authors.forename: Bernd
authors.initials: B
authors.lastname: Wissinger
authors.forename: Masoud
authors.initials: M
authors.lastname: Garshasbi
mesh_terms: D000293:Adolescent; D000818:Animals; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D020125:Mutation, Missense; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics*; D017434:Protein Structure, Tertiary; D017385:Sequence Homology
chemical_list: D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human