Extremely low penetrance of Leber's hereditary optic neuropathy in 8 Han Chinese families carrying the ND4 G11778A mutation.
OBJECTIVE
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.


METHODS
Eight Han Chinese families with maternally transmitted LHON were studied using clinical, genetic, and molecular evaluations.


METHODS
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).


METHODS
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 LHON-associated 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.
Qu
Jia
J
School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang, China.
Zhou
Xiangtian
X
Zhang
Juanjuan
J
Zhao
Fuxin
F
Sun
Yan-Hong
YH
Tong
Yi
Y
Wei
Qi-Ping
QP
Cai
Wansi
W
Yang
Li
L
West
Constance E
CE
Guan
Min-Xin
MX
D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics; D002648:Child; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics; D005074:Evoked Potentials, Visual; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009245:NADH Dehydrogenase / Q000235:genetics*; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics*; D010375:Pedigree; D019683:Penetrance; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D014792:Visual Acuity; D014794:Visual Fields; D055815:Young Adult
D004272:DNA, Mitochondrial; C098483:NADH dehydrogenase subunit 4; D009245:NADH Dehydrogenase