title: Accelerated reproductive aging in females lacking a novel centromere protein SYCP2L.
abstract: Menopause results from loss of ovarian function and marks the end of a woman's reproductive life. Alleles of the human SYCP2L locus are associated with age at natural menopause (ANM). SYCP2L is a paralogue of the synaptonemal complex protein SYCP2 and is expressed exclusively in oocytes. Here we report that SYCP2L localizes to centromeres of dictyate stage oocytes, which represent the limited pool of primordial oocytes that are formed perinatally and remain arrested till ovulation. Centromere localization of SYCP2L requires its C-terminal portion, which is missing in truncated variants resulting from low-frequency nonsense mutations identified in humans. Female mice lacking SYCP2L undergo a significantly higher progressive loss of oocytes with age compared with wild-type females and are less fertile. Specifically, the pool of primordial oocytes becomes more rapidly depleted in SYCP2L-deficient than in wild-type females, such that with aging, fewer oocytes undergo maturation in developing follicles. We find that a human SYCP2L intronic single nucleotide polymorphism (SNP) rs2153157, which is associated with ANM, changes the splicing efficiency of U12-type minor introns and may therefore regulate the steady-state amount of SYCP2L transcript. Furthermore, the more efficiently spliced allele of this intronic SNP in SYCP2L is associated with increased ANM. Our results suggest that SYCP2L promotes the survival of primordial oocytes and thus provide functional evidence for its association with ANM in humans.
authors.affiliation: Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Biology, University of Pennsylvania, 433 South University Avenue, Philadelphia, PA 19104, USA and.
authors.forename: Paula
authors.initials: P
authors.lastname: Stein
authors.affiliation: Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: N Adrian
authors.initials: NA
authors.lastname: Leu
authors.affiliation: Department of Biology, University of Pennsylvania, 433 South University Avenue, Philadelphia, PA 19104, USA and.
authors.forename: Lukáš
authors.initials: L
authors.lastname: Chmátal
authors.affiliation: Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jiangyang
authors.initials: J
authors.lastname: Xue
authors.affiliation: Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA, Department of Biology, University of Pennsylvania, 433 South University Avenue, Philadelphia, PA 19104, USA and.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Biology, University of Pennsylvania, 433 South University Avenue, Philadelphia, PA 19104, USA and.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lampson
authors.affiliation: Department of Biology, University of Pennsylvania, 433 South University Avenue, Philadelphia, PA 19104, USA and.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Schultz
authors.affiliation: Department of Biomedical Sciences, University of Pennsylvania School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA 19104, USA, pwang@vet.upenn.edu.
authors.forename: P Jeremy
authors.initials: PJ
authors.lastname: Wang
mesh_terms: D000375:Aging / Q000235:genetics; D000483:Alleles; D000818:Animals; D018929:Cell Culture Techniques; D018797:Cell Cycle Proteins; D002503:Centromere / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000172:deficiency / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D005260:Female; D005298:Fertility / Q000235:genetics; D006801:Humans; D008593:Menopause / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D009865:Oocytes / Q000378:metabolism*; D006080:Ovarian Follicle / Q000378:metabolism; D010053:Ovary / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D010060:Ovulation / Q000502:physiology; D020641:Polymorphism, Single Nucleotide; D012098:Reproduction / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C534707:SYCP2 protein, human; C498354:Sycp2 protein, mouse