OPA3, mutated in 3-methylglutaconic aciduria type III, encodes two transcripts targeted primarily to mitochondria.
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.
Huizing
Marjan
M
Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. mhuizing@mail.nih.gov
Dorward
Heidi
H
Ly
Lien
L
Klootwijk
Enriko
E
Kleta
Robert
R
Skovby
Flemming
F
Pei
Wuhong
W
Feldman
Benjamin
B
Gahl
William A
WA
Anikster
Yair
Y
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
D005977:Glutarates; C443108:OPA3 protein, human; D011506:Proteins; C022034:3-methylglutaconic acid