Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Targeted disruption of the p27(Kip1) gene caused ovulatory defects and female sterility. Maturation of secondary ovarian follicles into corpora lutea, which express high levels of p27, was markedly impaired. Furthermore a gene dose-dependent increase in animal size without other gross morphologic abnormalities was observed. All tissues were enlarged and contained more cells, although endocrine abnormalities were not evident. Thus, p27 deficiency may cause a cell-autonomous defect resulting in enhanced proliferation in response to mitogens. That p27 and Rb function in the same regulatory pathway was suggested by the finding that p27 deletion, like deletion of the Rb gene, uniquely caused neoplastic growth of the pituitary pars intermedia (Fero et al. (1996) Nakayama et al. (1996).

Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: p27kip1 (Cdkn1b) controls ovarian development by suppressing follicle endowment and activation, and promoting follicle atresia in mice. Rajareddy S et al. In humans, the molecular mechanisms underlying ovarian follicle endowment and activation, which are closely related to the control of female reproduction, occurrence of menopause, and related diseases such as premature ovarian failure (POF), are poorly understood. In the current study, we provide several lines of genetic evidence that the cyclin-dependent kinase inhibitor 1B (Cdkn1b, commonly known as p27(kip1) or p27) controls ovarian development in mice by suppressing follicle endowment and activation, and by promoting follicle death. In p27-deficient (p27(-/-)) mice, postnatal follicle assembly was accelerated, and the number of endowed follicles was doubled as compared to p27(+/+) mice. Moreover, in p27(-/-) ovaries the primordial follicle pool was prematurely activated once it was endowed, and at the same time the massive follicular death that occurs before sexual maturity was rescued by loss of p27. In early adulthood, however, the overactivated follicular pool in p27(-/-) ovaries was largely depleted, causing POF. Furthermore, we have extensively studied the molecular mechanisms underlying the above-mentioned phenotypes seen in p27(-/-) ovaries and have found that p27 controls follicular development by several distinct mechanisms at different stages of development of the ovary. For example, p27 controls oocyte growth by suppressing the functions of Cdk2/Cdc2-cyclin A/E1 in oocytes that are arrested at the diplotene stage of meiosis I. This function of p27 is distinct from its well-known role as a suppressor of cell cycle progression. In addition, we have found that p27 activates the caspase-9 - caspase-3 - caspase-7 - poly (ADP-ribose) polymerase (PARP) apoptotic cascade by inhibiting Cdk2/Cdc2-cyclin A/B1 kinase activities in follicles, thereby inducing follicle atresia. Our results suggest that the p27 gene is important in determining mammalian ovarian development. This study therefore provides insight into ovary-borne genetic aberrations that cause defects in folliculogenesis and infertility in humans.

Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: Increased number of multi-oocyte follicles (MOFs) in juvenile p27Kip1 mutant mice: potential role of granulosa cells. P?z-Sanz J et al. STUDY QUESTION: Why are female mice that lack a functional p27 protein infertile? SUMMARY ANSWER: The absence of a functional p27 leads to a dramatic increase in the number of multi-oocyte follicles (MOFs) in juvenile female mice; p27 would promote the individualization of follicles favoring the development of fertile eggs. WHAT IS KNOWN ALREADY: p27-/- female mice are infertile. p27 suppresses excessive follicular endowment and activation and promotes follicular atresia in mice. MATERIALS AND METHODS: Ovaries from wild type (WT) and p27Kip1 mutant mice aged 2, 4 and 12 weeks were subjected to immunohistochemistry/immunofluorescence. The slides with whole organs serially sectioned were scanned and examined by image analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with WT, p27Kip1 mutant pre-pubertal mice had a greater number of oocytes, a greater number of growing follicles and a greater number of MOFs. These differences were statistically significant (P < 0.05), particularly in the case of MOFs (P > 0.001). The unusually large number of MOFs in juvenile p27-deficient mice is a novel observation. In WT mice p27 protein remains present in the oocyte nucleus but gradually decreases in the ooplasm during follicular growth, while granulosa cells show dynamic, follicle stage-related changes. LIMITATIONS, REASONS FOR CAUTION: These results have been obtained in mice and they cannot be directly extrapolated to humans. WIDER IMPLICATIONS OF THE FINDINGS: The dramatic increase in the numbers of MOFs in juvenile p27 mutants has not been previously reported. The number of MOFs declines sharply as the mice become sexually mature, pointing to their negative selection. These findings open a new approach to the study of sterility. STUDY FUNDING/COMPETING INTERESTS: This study has been funded by the Basque Government, Dept. of Health grant 2007111063 and Dept. of Industry (Saiotek) grant S-PC11UN008. Jairo Perez-Sanz was the recipient of a grant from Fundaci?es? Gangoiti Barrera. The authors have no conflicts of interest to declare.

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Mutational analysis of SKP2 and P27 in Chinese Han women with premature ovarian failure. Zhao Z 2013 et al. P27 and SKP2, a major regulator of P27, play a crucial role in ovarian function in mice. Both P27-deficient and SKP2-deficient female mice develop premature ovarian failure (POF). The coding regions of SKP2 and P27 were examined in 200 Chinese women with POF and 200 control volunteers. This study is the first to investigate SKP2 in POF. No plausible pathogenic mutations were detected. The results suggest that mutations in SKP2 and P27 are not common in Chinese Han women with POF. P27 and Skp2, a major regulator of P27, play a crucial role in ovarian function in mice. Both P27-deficient and Skp2-deficient female mice develop premature ovarian failure (POF). The coding region of SKP2 and P27 were examined in 200 Chinese women with POF and 200 control volunteers. One known single-nucleotide polymorphism (SNP), rs6175530 in exon 7 of SKP2, and one known SNP, rs1690837 in exon 1 of P27, were identified. The present study is the first to discover variants occurring in SKP2 in association with POF. The results suggest that mutations in SKP2 and P27 are not common in Chinese Han women with POF. /////////////////////////