Extremely Low Penetrance of Leber's Hereditary Optic Neuropathy in 8 Han Chinese Families Carrying the ND4 G11778A Mutation

Abstract

Purpose-To investigate the role of mitochondrial haplotypes in the development of Leber's hereditary optic neuropathy (LHON) associated with the ND4 G11778A mutation in Chinese families. Design-EightHan Chinese families with maternally transmitted LHON were studied using clinical, genetic, and molecular evaluations.Participants-One hundred sixty-seven subjects from 8 Chinese families with a wide age range and severity of visual impairment.Methods-All subjects underwent the clinical and genetic evaluation, as well as molecular analysis of mitochondrial DNA (mtDNA).Main Outcome Measures-The ophthalmologic examinations included visual acuity, visual field examination, visual evoked potentials, and fundus photography. Mitochondrial DNA analysis included the polymerase chain reaction amplification of the entire mtDNA and subsequent sequence determination.Results-Eight families exhibited extremely low penetrance of visual impairment, with the average of 13%. In particular, 14 (12 males and 2 females) of 119 matrilineal relatives in these families exhibited the variable severity and age at onset in visual dysfunction. The average age of onset of vision loss was 17 years. Molecular analysis of mtDNA identified the homoplasimic ND4 G11778A mutation and distinct sets of variants belonging to the Asian haplogroups M8a2, D4g2, B4a1c, B5b, N9a1, D4b2b, C, and M7b1. However, there was an absence of secondary LHONassociated mtDNA mutations in these 8 Chinese families. Conclusions-The extremely low penetrance of vision loss in these 8 Chinese pedigrees strongly indicates that the G11778A mutation was itself insufficient to produce a clinical phenotype. The absence of secondary LHON mtDNA mutations suggest that these mtDNA haplogroup-specific variants may not play an important role in the phenotypic expression of the G11778A mutation in those Chinese families with very low penentrace of vision loss. However, nuclear backgrounds and environmental factors seem to be modifying factors for the phenotypic manifestation of the G11778A mutation in these Chinese families.Leber's hereditary optic neuropathy (LHON) is a maternally inherited disorder leading to the rapid, painless, and bilateral loss of central vision. [1][2][3][4] Mutations in mitochondrial DNA (mtDNA) are the molecular bases for this disorder. [5][6][7] Of these, the ND1 G3460A, ND4 G11778A, and ND6 T14484C mutations, which involve genes encoding the subunits of respiratory chain complex I, account for more than 50% of LHON pedigrees worldwide. [8][9][10] Those LHON-associated mtDNA mutations, unlike other pathogenic mtDNA mutations such as the Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes (MELAS)-associated tRNA Leu(UUR) A3243G mutation present in heteroplasmy (mixture of mutated and wild-type molecules), 11 often occur nearly homoplasmy or homoplasmy. Such mtDNA mutations as the G11778A mutation often exhibit incomplete penetrance because some individuals carrying the mutations have normal vision. 4,8,10,12 In addition, matrilineal ...

Leber's Hereditary Optic Neuropathy Is Associated with the T3866C Mutation in MitochondrialND1Gene in Three Han Chinese Families

“…Conversely, the average age at onset of visual impairment in the other 11 Chinese pedigrees, 66 and 49 Caucasian pedigrees carrying the G11778A mutation was 18, 24, and 28 years, respectively. 2,11,16,26,40,41 In addition, the ratio between affected male and female matrilineal relatives is 3:1, 0:1, 0:1 in these Chinese families, whereas this ratio ranged from 2:1 to 6:0 in 11 Chinese families 16,21,42 and were 4.5:1 and 3.7:1 in two large cohorts of Caucasian pedigrees carrying the G11778A mutation, respectively. 2,11,43 These data strongly indicate that the T3866C mutation is necessary but that by itself is insufficient to induce a clinical expression of LHON, as in the cases of the G11778A, T141484C, and T12338C mutations.…”

“…As shown in Table 1, 10 of 41 matrilineal relatives in these three Chinese families carrying the T3866C mutation exhibited visual impairment, while the average penetrances of visual impairment in the other 11 Chinese pedigrees carrying the G11778A mutation were 19.2%. 16,26,40 Furthermore, the average age at onset for visual impairment in these three Chinese families was 5, 11, and 24 years of age, respectively. Conversely, the average age at onset of visual impairment in the other 11 Chinese pedigrees, 66 and 49 Caucasian pedigrees carrying the G11778A mutation was 18, 24, and 28 years, respectively.…”

“…2,11,43 These data strongly indicate that the T3866C mutation is necessary but that by itself is insufficient to induce a clinical expression of LHON, as in the cases of the G11778A, T141484C, and T12338C mutations. 13,14,16,18,23 Therefore, the modifier factors should contribute to the phenotypic manifestation of T3866C mutation.…”

“…Therefore, he exhibited a typical clinical feature of LHON. Seven of the other 27 matrilineal relatives experienced loss of vision with the average of age at onset of 24 years, the age range being Superscript reference citation numbers refer to studies from which data were derived: Qu et al, 41 Qian et al, 42 and Qu et al 16 * Penetrance: affected matrilineal relatives/total matrilineal relatives.…”

Maternally Inherited Essential Hypertension Is Associated With the Novel 4263A>G Mutation in the Mitochondrial tRNA Ile Gene in a Large Han Chinese Family

“…Indeed, the incomplete penetrance of other clinical abnormalities arises from homoplasmic mtDNA mutations such as hypertensionassociated mtDNA 4435AϾG and 4401AϾG mutations, 15,16 deafness-associated 12S rRNA 1555AϾG mutation, 45 and Leber's hereditary optic neuropathy-associated ND4 11778GϾA mutation. 46 These homoplasmic mtDNA mutations only exhibited mild mitochondrial dysfunction. 15,16,45,47 The other modifier factors such as nuclear modifier genes, environmental and epigenetic factors, and personal lifestyles 43,48 may also contribute to the development of hypertension in these subjects carrying the 4263AϾG mutation.…”