title: OPA3, mutated in 3-methylglutaconic aciduria type III, encodes two transcripts targeted primarily to mitochondria.
abstract: 3-Methylglutaconic aciduria type III (3-MGCA type III), caused by recessive mutations in the 2-exon gene OPA3, is characterized by early-onset bilateral optic atrophy, later-onset extrapyramidal dysfunction, and increased urinary excretion of 3-methylglutaconic acid and 3-methylglutaric acid. Here we report the identification of a novel third OPA3 coding exon, the apparent product of a segmental duplication event, resulting in two gene transcripts, OPA3A and OPA3B. OPA3A deficiency (as in optic atrophy type 3) causes up-regulation of OPA3B. OPA3 protein function remains unknown, but it contains a putative mitochondrial leader sequence, mitochondrial sorting signal and a peroxisomal sorting signal. Our green fluorescent protein tagged OPA3 expression studies found its localization to be predominantly mitochondrial. These findings thus place the cellular metabolic defect of 3-MGCA type III in the mitochondrion rather than the peroxisome and implicate loss of OPA3A rather than gain of OPA3B in disease etiology.
authors.affiliation: Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. mhuizing@mail.nih.gov
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
authors.forename: Heidi
authors.initials: H
authors.lastname: Dorward
authors.forename: Lien
authors.initials: L
authors.lastname: Ly
authors.forename: Enriko
authors.initials: E
authors.lastname: Klootwijk
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.forename: Flemming
authors.initials: F
authors.lastname: Skovby
authors.forename: Wuhong
authors.initials: W
authors.lastname: Pei
authors.forename: Benjamin
authors.initials: B
authors.lastname: Feldman
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.forename: Yair
authors.initials: Y
authors.lastname: Anikster
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics* / Q000652:urine; D000595:Amino Acid Sequence; D005091:Exons; D005977:Glutarates / Q000652:urine*; D006801:Humans; D008928:Mitochondria / Q000235:genetics*; D008969:Molecular Sequence Data; D015418:Optic Atrophies, Hereditary / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D016415:Sequence Alignment
chemical_list: D005977:Glutarates; C443108:OPA3 protein, human; D011506:Proteins; C022034:3-methylglutaconic acid