Leber's hereditary optic neuropathy affects only female matrilineal relatives in two Chinese families.
OBJECTIVE
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.
Qu
Jia
J
School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou, Zhejiang, China. jqu@wzmc.net
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
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000818:Animals; D044466:Asian People / Q000235:genetics*; D002681:China / Q000453:epidemiology; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D054629:Genome, Mitochondrial; D006801:Humans; D008297:Male; D009245:NADH Dehydrogenase / Q000235:genetics; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics*; D010375:Pedigree; D010802:Phylogeny; D016133:Polymerase Chain Reaction; D012737:Sex Factors; D055815:Young Adult
D004272:DNA, Mitochondrial; C098483:NADH dehydrogenase subunit 4; D009245:NADH Dehydrogenase