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Leber's hereditary optic neuropathy affects only female matrilineal relatives in two Chinese families.

ABSTRACT: PURPOSE:The purpose of this study was to investigate the role of modifier factors in the expression of Leber's hereditary optic neuropathy (LHON). METHODS:Thirty-five subjects from two Han Chinese families with maternally transmitted LHON underwent a clinical and genetic evaluation and molecular analysis of mitochondrial (mt)DNA. RESULTS:Matrilineal relatives in the two Chinese families exhibited a wide range of severity in visual impairment, from blindness to nearly normal vision. Very strikingly, all nine affected individuals of 21 matrilineal relatives (13 females/8 males) were female, which translates to 33% and 57% of penetrance for optic neuropathy in the two families. The average age at onset was 22 and 25 years. These observations were in contrast with typical features in many LHON pedigrees that have a predominance of affected males. Molecular analysis of their mtDNAs identified the homoplasmic ND4 G11778A mutation and distinct sets of variants belonging to the Asian haplogroups M1 and M10a. Of other variants, the L175F variant in CO3; the I58V variant in ND6; and the I189V, L292R, and S297A variants in CYTB were located at highly conserved residues of polypeptides. CONCLUSIONS:Only female matrilineal relatives with a wide range of penetrance, severity, and age at onset of optic neuropathy in these two Chinese pedigrees showed the involvement of X-linked or autosomal recessive modifier genes in the phenotypic manifestation of the G11778A mutation. Furthermore, mitochondrial haplogroup-specific variants, together with epigenetic and environmental factors, may contribute to the phenotypic manifestation of the primary LHON-associated G11778A mutation in these pedigrees.

SUBMITTER: Qu J

PROVIDER: S-EPMC3066600 | biostudies-other | 2010 Oct

REPOSITORIES: biostudies-other

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Leber's hereditary optic neuropathy affects only female matrilineal relatives in two Chinese families.

Qu Jia J Wang Ying Y Tong Yi Y Zhou Xiangtian X Zhao Fuxin F Yang Li L Zhang Shoukang S Zhang Juanjuan J West Constance E CE Guan Min-Xin MX

Investigative ophthalmology & visual science 20100430 10

<h4>Purpose</h4>The purpose of this study was to investigate the role of modifier factors in the expression of Leber's hereditary optic neuropathy (LHON).<h4>Methods</h4>Thirty-five subjects from two Han Chinese families with maternally transmitted LHON underwent a clinical and genetic evaluation and molecular analysis of mitochondrial (mt)DNA.<h4>Results</h4>Matrilineal relatives in the two Chinese families exhibited a wide range of severity in visual impairment, from blindness to nearly normal ...[more]

PMID: 20435583

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Project description:PurposeTo 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.DesignEight Han Chinese families with maternally transmitted LHON were studied using clinical, genetic, and molecular evaluations.ParticipantsOne hundred sixty-seven subjects from 8 Chinese families with a wide age range and severity of visual impairment.MethodsAll subjects underwent the clinical and genetic evaluation, as well as molecular analysis of mitochondrial DNA (mtDNA).Main outcome measuresThe 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.ResultsEight 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 LHON-associated mtDNA mutations in these 8 Chinese families.ConclusionsThe 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.

Dataset Information

Leber's hereditary optic neuropathy affects only female matrilineal relatives in two Chinese families.

Publications

Leber's hereditary optic neuropathy affects only female matrilineal relatives in two Chinese families.

Similar Datasets

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