title: Mutation spectrum and splicing variants in the OPA1 gene.
abstract: Optic atrophy type 1 (OPA1, MIM 165500) is a dominantly inherited optic neuropathy that features low visual acuity leading in many cases to legal blindness. We have recently shown, with others, that mutations in the OPA1 gene encoding a dynamin-related mitochondrial protein, underlie the dominant form of optic atrophy. Here we report that OPA1 has eight mRNA isoforms as a result of the alternative splicing of exon 4 and two novel exons named 4b and 5b. In addition, we screened a cohort of 19 unrelated patients with dominant optic atrophy by direct sequencing of the 30 OPA1 exons (including exons 4b and 5b) and found mutations in 17 (89%) of them of which 8 were novel. A majority of these mutations were truncative (65%) and located in exons 8 to 28, but a number of them were amino acid changes predominantly found in the GTPase domain (exons 8 to 15). We hypothesize that at least two modifications of OPA1 may lead to dominant optic atrophy, that is alteration in GTPase activity and loss of the last seven C-terminal amino acids that putatively interact with other proteins.
authors.affiliation: Inserm U. 254, 71, rue de Navacelles, 34090 Montpellier, France.
authors.forename: C
authors.initials: C
authors.lastname: Delettre
authors.forename: J M
authors.initials: JM
authors.lastname: Griffoin
authors.forename: J
authors.initials: J
authors.lastname: Kaplan
authors.forename: H
authors.initials: H
authors.lastname: Dollfus
authors.forename: B
authors.initials: B
authors.lastname: Lorenz
authors.forename: L
authors.initials: L
authors.lastname: Faivre
authors.forename: G
authors.initials: G
authors.lastname: Lenaers
authors.forename: P
authors.initials: P
authors.lastname: Belenguer
authors.forename: C P
authors.initials: CP
authors.lastname: Hamel
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D002893:Chromosomes, Human, Pair 3; D005091:Exons / Q000235:genetics; D016368:Frameshift Mutation; D020558:GTP Phosphohydrolases / Q000235:genetics*; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D020125:Mutation, Missense; D029241:Optic Atrophy, Autosomal Dominant / Q000209:etiology / Q000235:genetics*; D017354:Point Mutation; D011110:Polymorphism, Genetic; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid
chemical_list: D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human