Mitochondrial DNA content is decreased in autosomal dominant optic atrophy.
BACKGROUND
Autosomal dominant optic atrophy (ADOA) is the commonest form of inherited optic neuropathy. Mutations in the OPA1 gene encoding a dynamin-related mitochondrial protein underlie ADOA and may perturb the biogenesis and maintenance of mitochondria.


OBJECTIVE
To investigate the mutation spectrum of the OPA1 gene and assess alterations in mitochondrial content caused by OPA1 mutations.


METHODS
Sixteen Korean patients with clinically suspected ADOA were studied. The mutation spectrum of the OPA1 gene was analyzed by PCR single-strand conformation polymorphism and sequencing, and mitochondrial DNA (mtDNA) content was quantified by real-time PCR.


RESULTS
Eight different mutations were found, including five novel mutations. Quantitative real-time PCR analysis showed excellent linearity and precision for the determination of mtDNA copy numbers. The number of mtDNA copies per cell in patients with OPA1 gene mutations (ages 7 to 40) was significantly lower than those in all normal control subjects (p = 0.037), particularly lower than in normal control subjects ages 10 to 39 (p = 0.022).


CONCLUSIONS
The mutation spectrum of the OPA1 gene disclosed marked genetic heterogeneity and the mitochondrial DNA content was found to be lower in autosomal dominant optic neuropathy, which provides direct evidence for a pathogenetic role of mutations of the OPA1 gene.
Kim
J Y
JY
Department of Laboratory Medicine, Seoul National University College of Medicine and Seoul National University Hospital Clinical Research Institute, and Seoul Seobu Blood Center, Korean Red Cross, Seoul, Korea.
Hwang
J-M
JM
Ko
H S
HS
Seong
M-W
MW
Park
B-J
BJ
Park
S S
SS
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D017398:Alternative Splicing / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D018628:Gene Dosage / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D011110:Polymorphism, Genetic / Q000235:genetics
D004272:DNA, Mitochondrial; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human