title: OPA1 (Kjer type) dominant optic atrophy: a novel mitochondrial disease.
abstract: Dominant optic atrophy (DOA) is the most common form of inherited optic neuropathy. Although heterogeneous, a major locus has been mapped to chromosome 3q28 and the responsible gene, OPA1, was recently identified. OPA1 is a mitochondrial dynamin-related GTPase implicated in the formation and maintenance of the mitochondrial network. To date, 62 mutations have been identified in a total of 201 DOA patients. Most of them (90%) are distributed from exons 8 to 28 with a majority in the GTPase domain (54%). None were found in the alternatively spliced exons 4, 4b, and 5b. Half of them are truncative mutations (50%) with a frequent recurrent allele, c.2708delTTAG. Most missense mutations (81%) cluster within the putative GTPase domain. Various pathogenic mechanisms may play a role in OPA1 DOA. Truncative mutations in the N-terminal region and perhaps missense mutations in the GTPase domain lead to a loss of function of the encoded protein and haplotype insufficiency. However, there is a cluster of truncation mutations in the in C-terminus, a putative dimerization domain, that could act through a dominant negative effect. The findings that OPA1-type DOA, as Leber optic neuropathy, is caused by the impairment of a mitochondrial protein address the question of the vulnerability of the retinal ganglion cell in response to mitochondrial defects.
authors.affiliation: Inserm U.254, Laboratoire de Neurobiologie de l'audition, 71, rue de Navacelles, 34090Montpellier, France. delettre@montp.inserm.fr
authors.forename: Cécile
authors.initials: C
authors.lastname: Delettre
authors.forename: Guy
authors.initials: G
authors.lastname: Lenaers
authors.forename: Laeticia
authors.initials: L
authors.lastname: Pelloquin
authors.forename: Pascale
authors.initials: P
authors.lastname: Belenguer
authors.forename: Christian P
authors.initials: CP
authors.lastname: Hamel
mesh_terms: D000818:Animals; D002893:Chromosomes, Human, Pair 3; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D028361:Mitochondrial Diseases / Q000235:genetics*; D009154:Mutation; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics*; D012165:Retinal Ganglion Cells / Q000502:physiology; D017384:Sequence Deletion
chemical_list: D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human