| 其他摘要 | Leber’s hereditary optic neuropathy (LHON; MIM 535000) is one of the most typical and common mitochondrial diseases, with a manifestation of painless, acute or subacute bilateral visual loss in midlife. Over 95% LHON patients was caused by one of three primary mutations (m.11778G>A, m.3460G>A and m.14484T>C). Incomplete penetrance and gender bias are two riddles of this disease. LHON is the most suitable modle for studying the mitochondrial disorders. In this thesis, we mainly studied the influence of mtDNA variants and halogroup on Chinese LHON patients with m.11778G>A and on suspected patients who expressed LHON clinical features but lacking the three primary mutations. We sequenced the mtDNA control region sequences for all patients and determined the entire mtDNA genomes of some patients. Each sample was classified into respective haplogroup based on the haplogroup sequence motif. Our recent study has shown that mtDNA background could affect the clinical expression of LHON in Chinese. Haplogroup M7b1’2 could increase the risk of vision loss but haplogroup M8a might produce a protective effect. However, frequencies of haplogroups M7b1'2 and M8a are not significantly altered in LHON pedigrees despite their apparent background effect on the penetrance. We analyzed the matrilineal structure of 479 Chinese patients with m.11778G>A (sample #1) and of 843 suspected LHON patients (sample #2) in order to discern the mtDNA background effect on disease onset. Haplogroup distribution frequency in the patient group was compared to that of the general Han Chinese population (n=1,689; sample #3). The results showed that the matrilineal composition of the suspected LHON cohort resembles that of the general Han Chinese population, suggesting no association with mtDNA haplogroups. However, the LHON sample with m.11778G>A differs from the general Han Chinese and suspected LHON sample populations significantly by harboring fewer lineages belonging to haplogroup F (#1 vs. #2, P=9.133×10-23, OR=0.062; #1 vs. #3, P=1.999×10-24, OR=0.066) and more lineages belonging to M7b (#1 vs. #2, adjuseted P=0.047, OR=1.795; #1 vs. #3, adjusted P=0.018, OR=1.782) and D4 (#1 vs. #2, adjusted P=0.031, OR=1.628 and #1 vs. #3, P=0.085, OR=1.467). The mtDNA mutations could affect LHON onset. Co-occurrence of m.11778G>A and m.1555A>G in one LHON pedigree could increase LHON penetrance. The mutation m.3635G>A might be one of the rare pathogenic mutations in the LHON patients lacking the three primary mutaions. In addition, we observed an obviously higher frequency (2.92%, 14/479) of m.593T>C in the MT-TF gene in the LHON patients than in suspected LHON patients (1.42%, 12/843) or in general population (2.06%, 49/2374). We analyzed the conservation of m.593T>C, secondary structure prediction and in vitro transcription of the MT-TF gene. The results suggested that this variation changed the secondary structure of the MT-TF gene, further impaired synthetic ability of mitochondrial proteins, and involved in the onset of LHON with m.11778G>A. In summary, we analyzed the mtDNA variants and haplogroups in Chinese LHON patients with m.11778G>A and suspected LHON patients and identified that mtDNA variants/haplogroup can affect the onset of LHON. The results provided theoretical basis and data for genetic counselling and clinical prevention of LHON. |
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