title: CSB-PGBD3 Mutations Cause Premature Ovarian Failure.
abstract: Premature ovarian failure (POF) is a rare, heterogeneous disorder characterized by cessation of menstruation occurring before the age of 40 years. Genetic etiology is responsible for perhaps 25% of cases, but most cases are sporadic and unexplained. In this study, through whole exome sequencing in a non-consanguineous family having four affected members with POF and Sanger sequencing in 432 sporadic cases, we identified three novel mutations in the fusion gene CSB-PGBD3. Subsequently functional studies suggest that mutated CSB-PGBD3 fusion protein was impaired in response to DNA damage, as indicated by delayed or absent recruitment to damaged sites. Our data provide the first evidence that mutations in the CSB-PGBD3 fusion protein can cause human disease, even in the presence of functional CSB, thus potentially explaining conservation of the fusion protein for 43 My since marmoset. The localization of the CSB-PGBD3 fusion protein to UVA-induced nuclear DNA repair foci further suggests that the CSB-PGBD3 fusion protein, like many other proteins that can cause POF, modulates or participates in DNA repair.
authors.affiliation: Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory for Reproductive Endocrinology of Ministry of Education, Jinan, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory for Reproductive Endocrinology of Ministry of Education, Jinan, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Guo
authors.affiliation: Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory for Reproductive Endocrinology of Ministry of Education, Jinan, China.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Li
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Tie-Shan
authors.initials: TS
authors.lastname: Tang
authors.affiliation: Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory for Reproductive Endocrinology of Ministry of Education, Jinan, China.
authors.forename: Shidou
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory for Reproductive Endocrinology of Ministry of Education, Jinan, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Jiao
authors.affiliation: State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Gong
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Caixia
authors.initials: C
authors.lastname: Guo
authors.affiliation: Research and Global Programs March of Dimes Foundation, White Plains, New York, United States of America.
authors.forename: Joe Leigh
authors.initials: JL
authors.lastname: Simpson
authors.affiliation: Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, National Research Center for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory for Reproductive Endocrinology of Ministry of Education, Jinan, China; Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Zi-Jiang
authors.initials: ZJ
authors.lastname: Chen
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D045744:Cell Line, Tumor; D003057:Cockayne Syndrome / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008594:Menopause, Premature / Q000235:genetics*; D008875:Middle Aged; D050506:Mutant Chimeric Proteins / Q000235:genetics*; D000075223:Poly-ADP-Ribose Binding Proteins; D016649:Primary Ovarian Insufficiency / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D050506:Mutant Chimeric Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D011993:Recombinant Fusion Proteins; C574548:CSB-PGBD3 fusion protein, human; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes