Variation in OPA1 Does Not Explain the Incomplete Penetrance of Leber Hereditary Optic Neuropathy

Overview

Journal Mol Vis

Specialties Cell Biology
Molecular Biology
Ophthalmology

Date 2011 Jan 5

PMID 21203403

Citations 2

Authors

Gavin Hudson

Patrick Yu-Wai-Man

Phillip G Griffiths

Leonardo Caporali

Solange S Salomao

Adriana Berezovsky

Valerio Carelli

Massimo Zeviani

Patrick F Chinnery

Affiliations

Soon will be listed here.

Abstract

Purpose: Leber hereditary optic neuropathy (LHON) is a common cause of inherited blindness, primarily due to one of three mitochondrial DNA (mtDNA) mutations. These mtDNA pathogenic mutations have variable clinical penetrance. Recent linkage evidence raised the possibility that the nuclear gene optic atrophy 1 (OPA1) determines whether mtDNA mutation carriers develop blindness. To validate these findings we studied OPA1 in three independent LHON cohorts: sequencing the gene in discordant male sib pairs, carrying out a family-based association study of common functional genetic variants, and carrying out a population-based association study of the same genetic variants.

Methods: We tested 3 hypothesis in three separate study groups. Study group 1: Direct sequencing of OPA1 coding regions was performed using sequencing methodologies (Applied Biosystems, Foster City, CA). Chromatograms were compared with the GenBank reference sequence NM_015560.1. Splice-site prediction was performed using GeneSplicer. Study group 2: Genotyping for rs166850 and rs10451941 was performed by restriction fragment length polymorphism (RFLP) analysis with specific primers for both genotypes, using The restriction enzymes RsaI and FspBI to discriminate genotypes. Study group 3: Genotyping for rs166850 and rs10451941 was performed by primer extension of allele-specific extensions products by matrix-associated laser desorption/ionisation time-of-flight (MALDI-TOF, Seqeunom, San Diego, CA) mass spectrometry. Allele and genotype frequencies were compared using Pearson's chi-square test. Multiple logistic regression was performed to look for interactions between the variables. All analyses were performed using SPSS software version 17.0 (SPSS Inc.).

Results: In all three groups we were unable to find an association between OPA1 genetic variation and visual failure in LHON mtDNA mutation carriers.

Conclusions: Our findings suggest that genetic variation in OPA1 is unlikely to make a major contribution to the risk of blindness in LHON mutation carriers.

Citing Articles

Dominant Optic Atrophy: Diagnostic Approach in the Pediatric Population.

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PMID: 36661516 PMC: 9857649. DOI: 10.3390/cimb45010030.

Modeling Retinal Ganglion Cell Dysfunction in Optic Neuropathies.

Porciatti V, Chou T Cells. 2021; 10(6).

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