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M. Zhang, H. Shi, C. Pang, Y. Chang, S. Xie, A. Mao, J. Cao, L. Wu; Genotype-Phenotype and Penetrance Analysis of Mitochondrial DNA Mutations in 36 Chinese Families With Leber’s Hereditary Optic Neuropathy. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3232.
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© ARVO (1962-2015); The Authors (2016-present)
Primary mitochondrial DNA (mtDNA) mutations at nucleotide positions of G11778A, T14484C and G3460A are response for approximately 95% cases of Leber hereditary optic neuropathy (LHON). In this study, we analyze the genotype-phenotype correlation of these mutation hotspots in Chinese LHON families.
Thirty-six LHON pedigrees were established in Xingtai Eye Hospital. The 284 individuals (127 male, 157 female) from these families were consent to participate in this study. The blood samples from affected and unaffected family members were collected and processed in Department of Molecular Inheritance, Zhognshan University Eye Center for mtDNA mutation screening. The DNAs were obtained thought phenol-chloroform extraction. Heteroduplex and Single-Strand Conformational Polymorphism (SSCP) were applied to examine mutated mtDNA sequence with specific designed primers. Polymerase Chain Reaction (PCR) and direct automatic sequencing analyzer were utilized for mutation detection.
Among 36 LHON pedigrees, the mutations at nucleotide positions of G11778A, T14484C and G3460A were detected in 31 families (244 members), 3 families (29 members) and 2 families (11 members), respectively. The penetrance values of three mtDNA mutation hotspots were demonstrated 60% (77/127) in male and 38.2% (60/157) in female. Furthermore, in 31 LHON pedigrees with G11778A mutation, 115 individuals of 244 members (109 male, 135 female) developed typical optic neuropathy and showed 47.13% phenotype penetrance. The penetrance values were 57.8% (63/109) in male and 38.5% (52/135) in female. In 3 LHON pedigrees with T14484C mutation, 16 individuals of 29 members (15 male, 14 female) were affected with a total of 55.17% phenotype penetrance. In this group, the penetrance value of 77.3% (11/15) in male was double higher than 35.7% (5/14) in female. In 2 LHON pedigrees with G3460A mutation, 6 individuals of 11 members (3 male, 8 female) were affected with phenotype of LHON (54.55% penetrance). In this group, the penetrance values were 100% (3/3) in male, which was almost triple higher than 37.5% (3/8) in female.
Three mtDNA mutation hotspots demonstrate 48.2% penetrance in Chinese LHON families. The penetrance is 2 - 3 folds higher in male than in female. The higher genotype-phenotype association suggests mtDNA mutation analysis provides definitive diagnosis and predictive factor of this disease in LHON families.
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