title: Mitochondrial haplogroup D4j specific variant m.11696G > a(MT-ND4) may increase the penetrance and expressivity of the LHON-associated m.11778G > a mutation in Chinese pedigrees.
abstract: Leber's hereditary optic neuropathy (LHON) is one of the most common mitochondrial disorders. We report here the clinical, genetic and molecular analysis of mitochondrial DNA (mtDNA) in eight Han Chinese families carrying the known mitochondrial 11778G > A(MT-ND4) mutation. Thirty-seven (26 males/11 females) of 77 matrilineal relatives in these families exhibited the variable severity and age-at-onset of optic neuropathy. The penetrances were from 25% to 75%, with the average of 42%, and the age-at-onset for visual impairment varied from 10 to 25 years, with the average of 17 in these Chinese pedigrees. Molecular analysis of their mtDNA identified distinct sets of variants belonging to the Eastern Asian haplogroupD4j. Except the known m.11778G > A mutation, the m.11696G > A(MT-ND4) mutation caused the substitution of an isoleucine for valineat amino acid position 313, located in a predicted transmembrane region of ND4. And, it is reported that the m.11696G > A mutation was associated with LHON, and appeared to contribute to higher penetrance in these nine Chinese families than other Chinese families carrying only the m.11778G > A mutation. Therefore, the mitochondrial haplogroup D4j specific m.11696G > A mutation may act in synergy with the primary LHON-associated m.11778G > A mutation, thereby increasing the penetrance and expressivity of visual loss in these Chinese families.
authors.affiliation: a Department of Ophthalmology , Xingtai Eye Hospital , Xingtai , Hebei , China.
authors.forename: Shipeng
authors.initials: S
authors.lastname: Xie
authors.affiliation: b Institute of Genetics , Zhejiang University School of Medicine , Hangzhou , Zhejiang , China.|c School of Ophthalmology and Optometry , Wenzhou Medical University , Wenzhou , Zhejiang , China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: b Institute of Genetics , Zhejiang University School of Medicine , Hangzhou , Zhejiang , China.
authors.forename: Jiji
authors.initials: J
authors.lastname: Sun
authors.affiliation: a Department of Ophthalmology , Xingtai Eye Hospital , Xingtai , Hebei , China.
authors.forename: Minglian
authors.initials: M
authors.lastname: Zhang
authors.affiliation: c School of Ophthalmology and Optometry , Wenzhou Medical University , Wenzhou , Zhejiang , China.|d Attardi Institute of Mitochondrial Biomedicine , Wenzhou Medical University , Wenzhou , Zhejiang , China.
authors.forename: Fuxin
authors.initials: F
authors.lastname: Zhao
authors.affiliation: e Department of Ophthalmology , Dongfang Hospital, Beijing University of Chinese Medicine and Pharmacology , Beijing , China.
authors.forename: Qi-Ping
authors.initials: QP
authors.lastname: Wei
authors.affiliation: c School of Ophthalmology and Optometry , Wenzhou Medical University , Wenzhou , Zhejiang , China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tong
authors.affiliation: c School of Ophthalmology and Optometry , Wenzhou Medical University , Wenzhou , Zhejiang , China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Liu
authors.affiliation: c School of Ophthalmology and Optometry , Wenzhou Medical University , Wenzhou , Zhejiang , China.
authors.forename: Xiangtian
authors.initials: X
authors.lastname: Zhou
authors.affiliation: b Institute of Genetics , Zhejiang University School of Medicine , Hangzhou , Zhejiang , China.|f Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases , Zhejiang University , Hangzhou , China.
authors.forename: Pingping
authors.initials: P
authors.lastname: Jiang
authors.affiliation: b Institute of Genetics , Zhejiang University School of Medicine , Hangzhou , Zhejiang , China.
authors.forename: Yanchun
authors.initials: Y
authors.lastname: Ji
authors.affiliation: a Department of Ophthalmology , Xingtai Eye Hospital , Xingtai , Hebei , China.|f Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases , Zhejiang University , Hangzhou , China.|g Division of Pathology , Cincinnati Children's Hospital Medical Center , Cincinnati , OH , USA.
authors.forename: Min-Xin
authors.initials: MX
authors.lastname: Guan
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics; D002648:Child; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics*; D029242:Optic Atrophy, Hereditary, Leber / Q000235:genetics / Q000378:metabolism*; D010375:Pedigree; D019683:Penetrance; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; C098483:NADH dehydrogenase subunit 4; D009245:NADH Dehydrogenase
keywords: Chinese; Leber's hereditary optic neuropathy; haplogroup; mitochondrial DNA; mutation