Sequence analysis of the complete mitochondrial genome in patients with Leber's hereditary optic neuropathy lacking the three most common pathogenic DNA mutations
Section snippets
Materials and methods
Patients. All patients included in the study showed typical clinical characteristics of LHON (Table 1). They had to fulfil the following criteria: no primary LHON mutation (np 3460, 11,778, and 14,484) found in routine screening, optic atrophy in both eyes (or, in the beginning peripapillary microangiopathy), central scotomas, vision of 0.1 or less, course of the disease of at least one year, evaluation/examination of all patients by the same clinician, and exclusion of other causes of
Results
The complete coding mitochondrial genome was analysed in 14 LHON patients (Table 2), lacking the three primary LHON mutations at np 3460, 11,778, and 14,484. Most differences relative to the reanalysed standard Cambridge sequence [6], [7] were known polymorphisms or were silent substitutions (http://www.gen.emory.edu/mitomap.html). In two patients, the rare LHON mutations 14,482 (patient #10) [9] and 14,568 (patient #1) [10], respectively, were confirmed.
The intermediate LHON mutation at np
Discussion
LHON has a strict maternal inheritance. The risk of developing the disease is inherited solely from the mother. Therefore, pathogenic mtDNA mutations are recognized as the primary cause and the predominant risk factor. But LHON is also characterized by incomplete penetrance and males are preferentially affected. So other factors seem to be required for the clinical manifestation and modification of the disease. These may include other genetic factors such as secondary mtDNA mutations, mutations
Acknowledgements
Sascha Fauser is supported by a grant from from the Federal Ministry of Education and Research (Fö. 01KS9602) and the Interdisciplinary Center of Clinical Research Tübingen (IZKF).
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