title: Increased Incidence of Mitochondrial Cytochrome C Oxidase 1 Gene Mutations in Patients with Primary Ovarian Insufficiency.
abstract: Primary ovarian insufficiency (POI), also known as premature ovarian failure (POF), is defined as more than six months of cessation of menses before the age of 40 years, with two serum follicle stimulating hormone (FSH) levels (at least 1 month apart) falling in the menopause range. The cause of POI remains undetermined in the majority of cases, although some studies have reported increased levels of reactive oxygen species (ROS) in idiopathic POF. The role of mitochondrial DNA in the pathogenesis of POI has not been studied extensively. This aim of this study was to uncover underlying mitochondrial genetic defects in patients with POI. The entire region of the mitochondrial genome was amplified in subjects with idiopathic POI (n=63) and age-matched healthy female controls (n=63) using nine pair sets of primers, followed by screening of the mitochondrial genome using an Illumina MiSeq. We identified a total of 96 non-synonymous mitochondrial variations in POI patients and 93 non-synonymous variations in control subjects. Of these, 21 (9 in POI and 12 in control) non-synonymous variations had not been reported previously. Eight mitochondrial cytochrome coxidase 1 (MT-CO1) missense variants were identified in POI patients, whereas only four missense mutations were observed in controls. A high incidence of MT-CO1 missense variants were identified in POI patients compared with controls, and the difference between the groups was statistically significant (13/63 vs. 5/63, p=0.042). Our results show that patients with primary ovarian insufficiency exhibit an increased incidence of mitochondrial cytochrome c oxidase 1 gene mutations, suggesting that MT-CO1 gene mutation may be causal in POI.
authors.affiliation: Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China; Genetic Diagnosis Lab Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, United States of America.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Zhen
authors.affiliation: Genetic Diagnosis Lab Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, United States of America.
authors.forename: Bailin
authors.initials: B
authors.lastname: Wu
authors.affiliation: Genetic Diagnosis Lab Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, United States of America; Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China.
authors.forename: Cuiling
authors.initials: C
authors.lastname: Lu
authors.affiliation: Genetic Diagnosis Lab Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, 02115, United States of America; Human Genetic Resource Center, National Research Institute for Health and Family Planning, Beijing, 100081, China.
authors.forename: Huafang
authors.initials: H
authors.lastname: Gao
authors.affiliation: Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Qiao
mesh_terms: D000328:Adult; D001483:Base Sequence; D004272:DNA, Mitochondrial / Q000235:genetics; D003576:Electron Transport Complex IV / Q000235:genetics*; D005260:Female; D050259:Genes, Mitochondrial / Q000235:genetics; D020022:Genetic Predisposition to Disease; D054629:Genome, Mitochondrial / Q000235:genetics; D006801:Humans; D008594:Menopause, Premature / Q000235:genetics*; D008928:Mitochondria / Q000201:enzymology / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D016649:Primary Ovarian Insufficiency / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV; C581860:cytochrome c oxidase subunit I, human