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Felix K. Jacobi, Beate Leo-Kottler, Karin Mittelviefhaus, Eberhart Zrenner, Jens Meyer, Carsten M. Pusch, Bernd Wissinger; Segregation Patterns and Heteroplasmy Prevalence in Leber’s Hereditary Optic Neuropathy. Invest. Ophthalmol. Vis. Sci. 2001;42(6):1208-1214.
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purpose. To investigate the segregation pattern of the mitochondrial DNA
mutation at nucleotide position 3460 responsible for Leber’s
hereditary optic neuropathy (LHON) and to determine the prevalence of
heteroplasmy for the three primary LHON mutations at positions 11778,
3460, and 14484.
methods. Segregation analysis was performed in a cross-sectional study by
determining the level of heteroplasmy in blood leukocytes of 23 LHON
patients and unaffected carriers from four unrelated families. One
family comprising two affected and three unaffected carriers was
followed over 5.5 years for a longitudinal segregation analysis of
heteroplasmy. The percentage of mutant mtDNA was determined using a
novel procedure of fluorescence-based primer extension and restriction
fragment length polymorphism analysis. The prevalence of heteroplasmy
was assessed by determining the number of genealogically unrelated LHON
pedigrees with heteroplasmic maternal family members from the LHON
patient records of the Department of Ophthalmology, University of
results. The authors observed a marked variability in the degree of heteroplasmy
levels within each pedigree and a tendency toward a higher mutant
allele frequency in offspring generations. Disease expression was
correlated with higher levels of mutant mtDNA molecules. Longitudinal
analysis revealed no statistically significant decrease in the
heteroplasmy level in the family studied but a reduction of 11% and
12% in one affected and one unaffected individual, respectively. In
167 genealogically unrelated LHON families the prevalence of
heteroplasmy was 5.6%, 40%, and 36.4% for the 11778, 3460, and 14484
LHON mutations, respectively.
conclusions. Cross-sectional studies of heteroplasmy for the 3460 LHON mutation
suggest that the genotype shifts toward a higher mutational load in
offspring generations. Long-term decrease in the blood mutant load in
single cases indicates negative selection of the mutant allele in the
hematopoietic cell system. The prevalence of heteroplasmy varies
significantly between the different primary LHON mutations, suggesting
genotypical differences in disease expression.
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