OPA1 mutations and mitochondrial DNA haplotypes in autosomal dominant optic atrophy.
OBJECTIVE
Autosomal dominant optic atrophy is a form of blindness, due in part to mutations affecting the mitochondrial-targeted OPA1 gene product. Both OPA1-positive and OPA1-negative families exhibit variable expressivity and incomplete penetrance. The purpose of this study was therefore to determine if the background mtDNA genotype acts as a genetic modifier for the expression of this disease.


METHODS
To find novel pathogenic OPA1 mutations, we performed complete OPA1 gene exon sequencing in 30 patients. To assess the possibility that mitochondrial DNA haplotype acts as a genetic modifier, we determined the mitochondrial DNA haplotype in 29 Caucasian OPA1-positive and OPA1-negative patients. Deviations in haplotype distribution between patient and control groups were determined by statistical means.


RESULTS
Seven new pathogenic OPA1 mutations were found. Most were detected in the mitochondrial targeting N-terminus or in the coiled-coil domain at the C-terminus. Mitochondrial DNA haplotype analysis indicated that the European haplogroup distribution was different between Caucasian patients and controls. Further, haplogroup J was three-fold over-represented in OPA1-negative patients.


CONCLUSIONS
Overall, our results support haploinsufficiency as a genetic mechanism in OPA1-positive cases and also suggest that mtDNA genetic background may influence disease expression in a subset of cases.
Han
Jian
J
Department of Basic Medical Sciences, Mercer University School of Medicine, Macon, GA, USA.
Thompson-Lowrey
Angela J
AJ
Reiss
Alyson
A
Mayorov
Vladimir
V
Jia
Haomiao
H
Biousse
Valerie
V
Newman
Nancy J
NJ
Brown
Michael D
MD
D000293:Adolescent; D000328:Adult; D002648:Child; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D029241:Optic Atrophy, Autosomal Dominant / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide
D004272:DNA, Mitochondrial; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human