Khan Nahid Akhtar, Govindaraj Periyasamy, Soumittra Nagasamy, Sharma Sonika, Srilekha Sundaramoorthy, Ambika Selvakumar, Vanniarajan Ayyasamy, Meena Angamuthu Kanikannan, Uppin Megha S, Sundaram Challa, Bindu Parayil Sankaran, Gayathri Narayanappa, Taly Arun B, Thangaraj Kumarasamy
Council of Scientific and Industrial Research, Centre for Cellular and Molecular Biology, Hyderabad, India.
Council of Scientific and Industrial Research, Centre for Cellular and Molecular Biology, Hyderabad, India 2Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, India 3Neuromuscular Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences, Bengaluru, India.
Invest Ophthalmol Vis Sci. 2017 Aug 1;58(10):3923-3930. doi: 10.1167/iovs.16-20695.
Leber's hereditary optic neuropathy (LHON; OMIM 535000) is one of the most common maternally inherited mitochondrial disorders. Three mitochondrial DNA point mutations-m.3460G>A (MT-ND1), m.11778G>A (MT-ND4), and m.14484T>C (MT-ND6)-account for the majority of reported LHON cases. Only approximately 50% of males and approximately 10% of females carrying these mutations develop optic neuropathy and blindness. Additional factors, such as mtDNA/nuclear genetic background and environmental modifiers, are likely to contribute toward the observed incomplete penetrance and gender bias. We aimed to investigate whether mtDNA haplogroup influences LHON clinical expression in Indian patients harboring the m.11778G>A mutation.
Detailed clinical assessment and complete mitochondrial genome sequencing was undertaken in 64 LHON families harboring the m.11778G>A mutation. Mitochondrial haplogroup was assigned based on evolutionarily conserved mtDNA variations.
A total of 543 individuals (295 male, 248 female) from 64 unrelated families harboring the m.11778G>A mutation were recruited to the study. The overall disease penetrance was 27.07% (146 of 543) and higher in males (37.9%; 112 of 295) than females (13.7%; 34 of 248). The mtDNA haplogroup analysis revealed that all affected probands belonged to different mtDNA haplogroups. No association between the m.11778G>A mutation and the background mtDNA haplogroup was detected.
The first detailed study of Indian LHON patients confirm that the m.11778G>A-related LHON in India coexists with multiple different mtDNA haplogroups, unlike the preferential association of west Eurasian haplogroup J and the reported increased clinical penetrance with the J2 subhaplogroup. However, we observed variable penetrance of LHON in different Indian mtDNA haplogroup backgrounds, indicating their possible influence on clinical expression. These data suggest that a similar heterogeneity, resulting from the mtDNA haplogroup, might also exist in other mitochondrial diseases among Indian populations.
Leber遗传性视神经病变（LHON；OMIM 535000）是最常见的母系遗传线粒体疾病之一。三种线粒体DNA点突变——m.3460G>A（MT-ND1）、m.11778G>A（MT-ND4）和m.14484T>C（MT-ND6）——占已报道LHON病例的大多数。携带这些突变的男性中只有约50%、女性中只有约10%会发展为视神经病变和失明。其他因素，如线粒体DNA/核基因背景和环境修饰因子，可能导致了观察到的不完全外显率和性别偏差。我们旨在研究线粒体DNA单倍群是否会影响携带m.11778G>A突变的印度患者的LHON临床表型。
对64个携带m.11778G>A突变的LHON家系进行了详细的临床评估和完整的线粒体基因组测序。根据进化上保守的线粒体DNA变异确定线粒体单倍群。
本研究招募了来自64个不相关家系、携带m.11778G>A突变的543名个体（295名男性，248名女性）。总体疾病外显率为27.07%（543例中的146例），男性（37.9%；295例中的112例）高于女性（13.7%；248例中的34例）。线粒体DNA单倍群分析显示，所有受影响的先证者属于不同的线粒体DNA单倍群。未检测到m.11778G>A突变与背景线粒体DNA单倍群之间的关联。
对印度LHON患者的首次详细研究证实，印度与m.11778G>A相关的LHON与多种不同的线粒体DNA单倍群共存，这与西欧亚单倍群J的优先关联以及报道的J2亚单倍群临床外显率增加不同。然而，我们观察到不同印度线粒体DNA单倍群背景下LHON的外显率存在差异，表明它们可能对临床表型有影响。这些数据表明，线粒体DNA单倍群导致的类似异质性可能也存在于印度人群的其他线粒体疾病中。
