OPA1 mutations and mitochondrial DNA haplotypes in autosomal dominant optic atrophy.

Abstract

PURPOSE:

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.

• Authors: Jian Han, Angela J Thompson-Lowrey, Alyson Reiss, Vladimir Mayorov, Haomiao Jia, Valerie Biousse, Nancy J Newman, Michael D Brown
• Journal: Genetics in medicine : official journal of the American College of Medical Genetics (Genet Med) Vol. 8 Issue 4 Pg. 217-25 (Apr 2006) ISSN: 1098-3600 [Print] United States
• PMID: 16617242 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Mitochondrial
• GTP Phosphohydrolases
• OPA1 protein, human

Topics

• Adolescent
• Adult
• Child
• DNA Mutational Analysis
• DNA, Mitochondrial
• Female
• GTP Phosphohydrolases (genetics)
• Haplotypes
• Heterozygote
• Humans
• Male
• Middle Aged
• Molecular Sequence Data
• Mutation
• Mutation, Missense
• Optic Atrophy, Autosomal Dominant (genetics)
• Polymorphism, Genetic
• Polymorphism, Single Nucleotide