Leber's hereditary optic neuropathy is associated with the T12338C mutation in mitochondrial ND5 gene in six Han Chinese families.
OBJECTIVE
To investigate the molecular pathogenesis of Leber's hereditary optic neuropathy (LHON) in Chinese families.


METHODS
Six Han Chinese families who seem to have maternally transmitted LHON were studied by clinical, genetic, and molecular evaluations.


METHODS
One hundred twenty-seven subjects from 6 Chinese families with a wide range of age-at-onset and severity of visual impairment.


METHODS
All subjects underwent clinical examination, genetic evaluation, and molecular analysis of mitochondrial DNA (mtDNA).


METHODS
The ophthalmologic examinations included visual acuity, visual field examination, visual evoked potentials, and fundus photography. The mtDNA analysis included the polymerase chain reaction (PCR) amplification of entire mtDNA and subsequent sequence determination.


RESULTS
Six families exhibited low penetrance of visual impairment, with an average of 10.8%. In particular, 9 (6 males/3 females) of 86 matrilineal relatives in these families exhibited variable severity and age at onset in visual dysfunction. The average age at onset of visual loss was 20 years. Molecular analysis of mtDNA in these families identified the homoplasmic ND5T12338C mutation and distinct set of variants belonging to the Asian haplogroup F2. The T12338C mutation is only present in the maternal lineage of those pedigrees and not in 178 Chinese controls. This mutation resulted in the replacement of the first amino acid, a translation-initiating methionine with a threonine, shortening 2 amino acids of ND5 polypeptide. The T12338C mutation is also located in 2 nucleotides adjacent to the 3' end of the tRNA(Leu(CUN)). Thus, this mutation may alter ND5 mRNA metabolism and the processing of RNA precursors. As a result, this mutation impairs respiratory function, leading to visual impairment.


CONCLUSIONS
Several lines of evidence suggest that the mitochondrial ND5T12338C mutation is associated with LHON. The tissue specificity of this mutation is likely due to the involvement of nuclear modifier genes. The identification of nuclear modifiers is important for the elucidation of the pathogenic mechanism of LHON and an open avenue for therapeutic interventions. The T12338C mutation should be added to the list of inherited risk factors for future molecular diagnosis. Our findings are helpful for counseling families with LHON.
School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang, China.
Xiao-Ling
XL
Liu
Xiangtian
X
Zhou
Jian
J
Zhou
Fuxin
F
Zhao
Juanjuan
J
Zhang
Chengwu
C
Li
Yanchun
Y
Ji
Yu
Y
Zhang
Qi-Ping
QP
Wei
Yan-Hong
YH
Sun
Li
L
Yang
Bing
B
Lin
Yumin
Y
Yuan
Yingzi
Y
Li
Jia
J
Qu
Min-Xin
MX
Guan
D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics*; D002648:Child; D002681:China / Q000208:ethnology; D004272:DNA, Mitochondrial / Q000235:genetics*; D042967:Electron Transport Complex I / Q000235:genetics*; D005074:Evoked Potentials, Visual / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics* / Q000503:physiopathology; D010375:Pedigree; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D014792:Visual Acuity / Q000502:physiology; D014794:Visual Fields / Q000502:physiology; D055815:Young Adult
D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; C481838:MT-ND5 protein, human; D042967:Electron Transport Complex I