Clinical Expression of Leber Hereditary Optic Neuropathy Is Affected by the Mitochondrial DNA–Haplogroup Background

Abstract

Leber hereditary optic neuropathy (LHON) is due primarily to one of three common point mutations of mitochondrial DNA (mtDNA), but the incomplete penetrance implicates additional genetic or environmental factors in the pathophysiology of the disorder. Both the 11778G-->A and 14484T-->C LHON mutations are preferentially found on a specific mtDNA genetic background, but 3460G-->A is not. However, there is no clear evidence that any background influences clinical penetrance in any of these mutations. By studying 3,613 subjects from 159 LHON-affected pedigrees, we show that the risk of visual failure is greater when the 11778G-->A or 14484T-->C mutations are present in specific subgroups of haplogroup J (J2 for 11778G-->A and J1 for 14484T-->C) and when the 3460G-->A mutation is present in haplogroup K. By contrast, the risk of visual failure is significantly less when 11778G-->A occurs in haplogroup H. Substitutions on MTCYB provide an explanation for these findings, which demonstrate that common genetic variants have a marked effect on the expression of an ostensibly monogenic mtDNA disorder.

Unsolved issues related to human mitochondrial diseases

“…The main candidate genetic modifiers have been the mtDNA haplogroup and nuclear genes encoding mtDNA replication factors [6,7]. Despite longstanding and intensive efforts in the case of LHON the modifying nuclear genes have however remained elusive [8][9][10].…”

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…It is a matter of debate whether the presence of polymorphisms in the mtDNA or in nuclear genes encoding RC components could modify the effects of a particular mutation on the biosynthesis and electron transfer properties of the RC complexes. In this regard, a genetic modifying role for the mtDNA haplogroup background has often been proposed in the clinical expression of LHON, a maternally-inherited blinding disease that constitutes the most common mitochondrial disorder (Brown et al, 1997;Carelli et al, 1997;Hofmann et al, 1997;Torroni et al, 1997;Brown et al, 2002;Carelli et al, 2006;Yen et al, 2006;Hudson et al, 2007;Carelli et al, 2009). An increased complex I-dependent ROS production and decreased antioxidant defenses have been reportedly…”

Mitochondrial disorders: aetiologies, models systems, and candidate therapies

“…Furthermore, certain mitochondrial backgrounds may modulate susceptibility to disease and this may be linked to variations in oxygen consumption, efficiency of electron transport, ATP generation, and reactive oxygen species (ROS) production [28]. Evidence suggests that for multifactorial disorders, such as AMD and Parkinson's disease (PD), specific mitochondrial haplogroups can aggravate or attenuate disease risk [29][30][31][32][33]. Evidence in support of mitochondrial haplogroups modulating disease is more compelling for disorders such as LHON and AMD than for PD and Huntington disease (HD), where equivocal findings have been reported.…”

“…LHON demonstrates many of the features of mitochondrial inheritance discussed in this review, with disease severity influenced by levels of heteroplasmy, mitochondrial haplogroups, nuclear modifier loci, and environmental factors. For example, the G11778A (ND4) and T14484C (ND6) LHON mutations on subgroups of a mitochondrial haplogroup J or the G3460A (ND1) mutation on the mitochondrial haplotype K background have been associated with increased risk of visual loss [29]. Differences between haplogroups may be partially due to mtDNA quantity, which influences OXPHOS capacity [30] and may account for gender differences in disease penetrance in LHON; there is a suggestion that oestrogens increase mtDNA levels, enhancing oxygen consumption and ATP generation [87].…”