Genomic Markers of Ovarian Reserve

Abstract

Ovarian reserve and its utilization, over a reproductive life span, are determined by genetic, epigenetic, and environmental factors. The establishment of the primordial follicle pool and the rate of primordial follicle activation have been under intense study to determine genetic factors that affect reproductive lifespan. Much has been learned from transgenic animal models about the developmental origins of the primordial follicle pool and mechanisms that lead to primordial follicle activation, folliculogenesis, and the maturation of a single oocyte with each menstrual cycle. Recent genome-wide association studies on the age of human menopause have identified approximately 20 loci, and shown the importance of factors involved in double-strand break repair and immunology. Studies to date from animal models and humans show that many genes determine ovarian aging, and that there is no single dominant allele yet responsible for depletion of the ovarian reserve. Personalized genomic approaches will need to take into account the high degree of genetic heterogeneity, family pedigree, and functional data of the genes critical at various stages of ovarian development to predict women's reproductive life span.

Keywords

ovarian reserve - menopause - premature ovarian failure

• References

• 1 Mathews TJ, Hamilton BE. Delayed childbearing: more women are having their first child later in life. NCHS Data Brief. Vol. 21. Centers for Disease Control and Prevention: U.S. Department of Health and Human Services; 2009
• 2 Milan A. Fertility: overview, 2009 to 2011. Report on the Demographic Situation in Canada. Component of Statistics Canada Catalogue no. 91-209-X. Government of Canada; 2013
• 3 Broekmans FJ, Soules MR, Fauser BC. Ovarian aging: mechanisms and clinical consequences. Endocr Rev 2009; 30 (5) 465-493
• 4 Rosen MP, Johnstone E, McCulloch CE , et al. A characterization of the relationship of ovarian reserve markers with age. Fertil Steril 2012; 97 (1) 238-243
• 5 Jagarlamudi K, Rajkovic A. Oogenesis: transcriptional regulators and mouse models. Mol Cell Endocrinol 2012; 356 (1–2) 31-39
• 6 Sarraj MA, Drummond AE. Mammalian foetal ovarian development: consequences for health and disease. Reproduction 2012; 143 (2) 151-163
• 7 Palma GA, Argañaraz ME, Barrera AD, Rodler D, Mutto AA, Sinowatz F. Biology and biotechnology of follicle development. Scientific World Journal 2012; 2012: 938138
• 8 Persani L, Rossetti R, Cacciatore C. Genes involved in human premature ovarian failure. J Mol Endocrinol 2010; 45 (5) 257-279
• 9 McGee EA, Hsueh AJ. Initial and cyclic recruitment of ovarian follicles. Endocr Rev 2000; 21 (2) 200-214
• 10 Johnson J, Canning J, Kaneko T, Pru JK, Tilly JL. Germline stem cells and follicular renewal in the postnatal mammalian ovary. Nature 2004; 428 (6979) 145-150
• 11 Li J, Kawamura K, Cheng Y , et al. Activation of dormant ovarian follicles to generate mature eggs. Proc Natl Acad Sci U S A 2010; 107 (22) 10280-10284
• 12 Jin M, Yu Y, Huang H. An update on primary ovarian insufficiency. Sci China Life Sci 2012; 55 (8) 677-686
• 13 Morris DH, Jones ME, Schoemaker MJ, Ashworth A, Swerdlow AJ. Familial concordance for age at natural menopause: results from the Breakthrough Generations Study. Menopause 2011; 18 (9) 956-961
• 14 Murabito JM, Yang Q, Fox C, Wilson PW, Cupples LA. Heritability of age at natural menopause in the Framingham Heart Study. J Clin Endocrinol Metab 2005; 90 (6) 3427-3430
• 15 van Asselt KM, Kok HS, Pearson PL , et al. Heritability of menopausal age in mothers and daughters. Fertil Steril 2004; 82 (5) 1348-1351
• 16 Snieder H, MacGregor AJ, Spector TD. Genes control the cessation of a woman's reproductive life: a twin study of hysterectomy and age at menopause. J Clin Endocrinol Metab 1998; 83 (6) 1875-1880
• 17 Simpson JL, Rajkovic A. Ovarian differentiation and gonadal failure. Am J Med Genet 1999; 89 (4) 186-200
• 18 Soyal SM, Amleh A, Dean J. FIGalpha, a germ cell-specific transcription factor required for ovarian follicle formation. Development 2000; 127 (21) 4645-4654
• 19 Bayne RA, Martins da Silva SJ, Anderson RA. Increased expression of the FIGLA transcription factor is associated with primordial follicle formation in the human fetal ovary. Mol Hum Reprod 2004; 10 (6) 373-381
• 20 Zhao H, Chen ZJ, Qin Y , et al. Transcription factor FIGLA is mutated in patients with premature ovarian failure. Am J Hum Genet 2008; 82 (6) 1342-1348
• 21 Huntriss J, Gosden R, Hinkins M , et al. Isolation, characterization and expression of the human Factor In the Germline alpha (FIGLA) gene in ovarian follicles and oocytes. Mol Hum Reprod 2002; 8 (12) 1087-1095
• 22 Pangas SA, Choi Y, Ballow DJ , et al. Oogenesis requires germ cell-specific transcriptional regulators Sohlh1 and Lhx8. Proc Natl Acad Sci U S A 2006; 103 (21) 8090-8095
• 23 Pangas SA. Regulation of the ovarian reserve by members of the transforming growth factor beta family. Mol Reprod Dev 2012; 79 (10) 666-679
• 24 Choi Y, Yuan D, Rajkovic A. Germ cell-specific transcriptional regulator sohlh2 is essential for early mouse folliculogenesis and oocyte-specific gene expression. Biol Reprod 2008; 79 (6) 1176-1182
• 25 Choi Y, Ballow DJ, Xin Y, Rajkovic A. Lim homeobox gene, lhx8, is essential for mouse oocyte differentiation and survival. Biol Reprod 2008; 79 (3) 442-449
• 26 Qin Y, Zhao H, Kovanci E, Simpson JL, Chen ZJ, Rajkovic A. Analysis of LHX8 mutation in premature ovarian failure. Fertil Steril 2008; 89 (4) 1012-1014
• 27 Suzumori N, Yan C, Matzuk MM, Rajkovic A. Nobox is a homeobox-encoding gene preferentially expressed in primordial and growing oocytes. Mech Dev 2002; 111 (1–2) 137-141
• 28 Rajkovic A, Pangas SA, Ballow D, Suzumori N, Matzuk MM. NOBOX deficiency disrupts early folliculogenesis and oocyte-specific gene expression. Science 2004; 305 (5687) 1157-1159
• 29 Lechowska A, Bilinski S, Choi Y, Shin Y, Kloc M, Rajkovic A. Premature ovarian failure in nobox-deficient mice is caused by defects in somatic cell invasion and germ cell cyst breakdown. J Assist Reprod Genet 2011; 28 (7) 583-589
• 30 Choi Y, Qin Y, Berger MF, Ballow DJ, Bulyk ML, Rajkovic A. Microarray analyses of newborn mouse ovaries lacking Nobox. Biol Reprod 2007; 77 (2) 312-319
• 31 Choi Y, Rajkovic A. Genetics of early mammalian folliculogenesis. Cell Mol Life Sci 2006; 63 (5) 579-590
• 32 Huntriss J, Hinkins M, Picton HM. cDNA cloning and expression of the human NOBOX gene in oocytes and ovarian follicles. Mol Hum Reprod 2006; 12 (5) 283-289
• 33 Qin Y, Choi Y, Zhao H, Simpson JL, Chen ZJ, Rajkovic A. NOBOX homeobox mutation causes premature ovarian failure. Am J Hum Genet 2007; 81 (3) 576-581
• 34 Bouilly J, Bachelot A, Broutin I, Touraine P, Binart N. Novel NOBOX loss-of-function mutations account for 6.2% of cases in a large primary ovarian insufficiency cohort. Hum Mutat 2011; 32 (10) 1108-1113
• 35 Sehested LT, Møller RS, Bache I , et al. Deletion of 7q34-q36.2 in two siblings with mental retardation, language delay, primary amenorrhea, and dysmorphic features. Am J Med Genet A 2010; 152A (12) 3115-3119
• 36 Rossi E, Verri AP, Patricelli MG , et al. A 12Mb deletion at 7q33-q35 associated with autism spectrum disorders and primary amenorrhea. Eur J Med Genet 2008; 51 (6) 631-638
• 37 Wang J, Wang B, Song J , et al. New candidate gene POU5F1 associated with premature ovarian failure in Chinese patients. Reprod Biomed Online 2011; 22 (3) 312-316
• 38 Nilsson EE, Kezele P, Skinner MK. Leukemia inhibitory factor (LIF) promotes the primordial to primary follicle transition in rat ovaries. Mol Cell Endocrinol 2002; 188 (1–2) 65-73
• 39 Barrios F, Filipponi D, Campolo F , et al. SOHLH1 and SOHLH2 control Kit expression during postnatal male germ cell development. J Cell Sci 2012; 125 (Pt 6) 1455-1464
• 40 Huang EJ, Manova K, Packer AI, Sanchez S, Bachvarova RF, Besmer P. The murine steel panda mutation affects kit ligand expression and growth of early ovarian follicles. Dev Biol 1993; 157 (1) 100-109
• 41 Kuroda H, Terada N, Nakayama H, Matsumoto K, Kitamura Y. Infertility due to growth arrest of ovarian follicles in Sl/Slt mice. Dev Biol 1988; 126 (1) 71-79
• 42 McCoshen JA, McCallion DJ. A study of the primordial germ cells during their migratory phase in Steel mutant mice. Experientia 1975; 31 (5) 589-590
• 43 Smith ER, Yeasky T, Wei JQ , et al. White spotting variant mouse as an experimental model for ovarian aging and menopausal biology. Menopause 2012; 19 (5) 588-596
• 44 Hui ES, Udofa EA, Soto J , et al. Investigation of the human stem cell factor KIT ligand gene, KITLG, in women with 46,XX spontaneous premature ovarian failure. Fertil Steril 2006; 85 (5) 1502-1507
• 45 John GB, Gallardo TD, Shirley LJ, Castrillon DH. Foxo3 is a PI3K-dependent molecular switch controlling the initiation of oocyte growth. Dev Biol 2008; 321 (1) 197-204
• 46 Reddy P, Liu L, Adhikari D , et al. Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool. Science 2008; 319 (5863) 611-613
• 47 John GB, Shidler MJ, Besmer P, Castrillon DH. Kit signaling via PI3K promotes ovarian follicle maturation but is dispensable for primordial follicle activation. Dev Biol 2009; 331 (2) 292-299
• 48 Edson MA, Nagaraja AK, Matzuk MM. The mammalian ovary from genesis to revelation. Endocr Rev 2009; 30 (6) 624-712
• 49 Sullivan SD, Castrillon DH. Insights into primary ovarian insufficiency through genetically engineered mouse models. Semin Reprod Med 2011; 29 (4) 283-298
• 50 Reddy P, Adhikari D, Zheng W , et al. PDK1 signaling in oocytes controls reproductive aging and lifespan by manipulating the survival of primordial follicles. Hum Mol Genet 2009; 18 (15) 2813-2824
• 51 Adhikari D, Risal S, Liu K, Shen Y. Pharmacological inhibition of mTORC1 prevents over-activation of the primordial follicle pool in response to elevated PI3K signaling. PLoS ONE 2013; 8 (1) e53810
• 52 Adhikari D, Gorre N, Risal S , et al. The safe use of a PTEN inhibitor for the activation of dormant mouse primordial follicles and generation of fertilizable eggs. PLoS ONE 2012; 7 (6) e39034
• 53 Zhao Z, Qin Y, Ma J , et al. PTEN gene analysis in premature ovarian failure patients. Acta Obstet Gynecol Scand 2011; 90 (6) 678-679
• 54 Shimizu Y, Kimura F, Takebayashi K, Fujiwara M, Takakura K, Takahashi K. Mutational analysis of the PTEN gene in women with premature ovarian failure. Acta Obstet Gynecol Scand 2009; 88 (7) 824-825
• 55 John GB, Shirley LJ, Gallardo TD, Castrillon DH. Specificity of the requirement for Foxo3 in primordial follicle activation. Reproduction 2007; 133 (5) 855-863
• 56 Liu L, Rajareddy S, Reddy P , et al. Infertility caused by retardation of follicular development in mice with oocyte-specific expression of Foxo3a. Development 2007; 134 (1) 199-209
• 57 Rajareddy S, Reddy P, Du C , et al. p27kip1 (cyclin-dependent kinase inhibitor 1B) controls ovarian development by suppressing follicle endowment and activation and promoting follicle atresia in mice. Mol Endocrinol 2007; 21 (9) 2189-2202
• 58 Halperin J, Devi SY, Elizur S , et al. Prolactin signaling through the short form of its receptor represses forkhead transcription factor FOXO3 and its target gene galt causing a severe ovarian defect. Mol Endocrinol 2008; 22 (2) 513-522
• 59 Wang B, Ni F, Li L , et al. Analysis of cyclin-dependent kinase inhibitor 1B mutation in Han Chinese women with premature ovarian failure. Reprod Biomed Online 2010; 21 (2) 212-214
• 60 Ojeda D, Lakhal B, Fonseca DJ , et al. Sequence analysis of the CDKN1B gene in patients with premature ovarian failure reveals a novel mutation potentially related to the phenotype. Fertil Steril 2011; 95 (8) 2658-2660 , e1
• 61 Gallardo TD, John GB, Bradshaw K , et al. Sequence variation at the human FOXO3 locus: a study of premature ovarian failure and primary amenorrhea. Hum Reprod 2008; 23 (1) 216-221
• 62 Solc P, Schultz RM, Motlik J. Prophase I arrest and progression to metaphase I in mouse oocytes: comparison of resumption of meiosis and recovery from G2-arrest in somatic cells. Mol Hum Reprod 2010; 16 (9) 654-664
• 63 Perry JR, Corre T, Esko T , et al; ReproGen Consortium. A genome-wide association study of early menopause and the combined impact of identified variants. Hum Mol Genet 2013; 22 (7) 1465-1472
• 64 Greenfeld CR, Pepling ME, Babus JK, Furth PA, Flaws JA. BAX regulates follicular endowment in mice. Reproduction 2007; 133 (5) 865-876
• 65 Perez GI, Jurisicova A, Wise L , et al. Absence of the proapoptotic Bax protein extends fertility and alleviates age-related health complications in female mice. Proc Natl Acad Sci U S A 2007; 104 (12) 5229-5234
• 66 Dong J, Albertini DF, Nishimori K, Kumar TR, Lu N, Matzuk MM. Growth differentiation factor-9 is required during early ovarian folliculogenesis. Nature 1996; 383 (6600) 531-535
• 67 Galloway SM, McNatty KP, Cambridge LM , et al. Mutations in an oocyte-derived growth factor gene (BMP15) cause increased ovulation rate and infertility in a dosage-sensitive manner. Nat Genet 2000; 25 (3) 279-283
• 68 Yan C, Wang P, DeMayo J , et al. Synergistic roles of bone morphogenetic protein 15 and growth differentiation factor 9 in ovarian function. Mol Endocrinol 2001; 15 (6) 854-866
• 69 Dixit H, Rao LK, Padmalatha V , et al. Mutational screening of the coding region of growth differentiation factor 9 gene in Indian women with ovarian failure. Menopause 2005; 12 (6) 749-754
• 70 Zhao H, Qin Y, Kovanci E, Simpson JL, Chen ZJ, Rajkovic A. Analyses of GDF9 mutation in 100 Chinese women with premature ovarian failure. Fertil Steril 2007; 88 (5) 1474-1476
• 71 Laissue P, Christin-Maitre S, Touraine P , et al. Mutations and sequence variants in GDF9 and BMP15 in patients with premature ovarian failure. Eur J Endocrinol 2006; 154 (5) 739-744
• 72 Kovanci E, Rohozinski J, Simpson JL, Heard MJ, Bishop CE, Carson SA. Growth differentiating factor-9 mutations may be associated with premature ovarian failure. Fertil Steril 2007; 87 (1) 143-146
• 73 Takebayashi K, Takakura K, Wang H, Kimura F, Kasahara K, Noda Y. Mutation analysis of the growth differentiation factor-9 and -9B genes in patients with premature ovarian failure and polycystic ovary syndrome. Fertil Steril 2000; 74 (5) 976-979
• 74 Dixit H, Rao LK, Padmalatha VV , et al. Missense mutations in the BMP15 gene are associated with ovarian failure. Hum Genet 2006; 119 (4) 408-415
• 75 Tiotiu D, Alvaro Mercadal B, Imbert R , et al. Variants of the BMP15 gene in a cohort of patients with premature ovarian failure. Hum Reprod 2010; 25 (6) 1581-1587
• 76 Lakhal B, Laissue P, Braham R , et al. A novel BMP15 variant, potentially affecting the signal peptide, in a familial case of premature ovarian failure. Clin Endocrinol (Oxf) 2009; 71 (5) 752-753
• 77 Di Pasquale E, Rossetti R, Marozzi A , et al. Identification of new variants of human BMP15 gene in a large cohort of women with premature ovarian failure. J Clin Endocrinol Metab 2006; 91 (5) 1976-1979
• 78 Zhang P, Shi YH, Wang LC, Chen ZJ. Sequence variants in exons of the BMP-15 gene in Chinese patients with premature ovarian failure. Acta Obstet Gynecol Scand 2007; 86 (5) 585-589
• 79 Chand AL, Ponnampalam AP, Harris SE, Winship IM, Shelling AN. Mutational analysis of BMP15 and GDF9 as candidate genes for premature ovarian failure. Fertil Steril 2006; 86 (4) 1009-1012
• 80 Voorhuis M, Broekmans FJ, Fauser BC, Onland-Moret NC, van der Schouw YT. Genes involved in initial follicle recruitment may be associated with age at menopause. J Clin Endocrinol Metab 2011; 96 (3) E473-E479
• 81 Kuo FT, Fan K, Bentsi-Barnes I, Barlow GM, Pisarska MD. Mouse forkhead L2 maintains repression of FSH-dependent genes in the granulosa cell. Reproduction 2012; 144 (4) 485-494
• 82 Laissue P, Lakhal B, Benayoun BA , et al. Functional evidence implicating FOXL2 in non-syndromic premature ovarian failure and in the regulation of the transcription factor OSR2. J Med Genet 2009; 46 (7) 455-457
• 83 Chatterjee S, Modi D, Maitra A , et al. Screening for FOXL2 gene mutations in women with premature ovarian failure: an Indian experience. Reprod Biomed Online 2007; 15 (5) 554-560
• 84 Bodega B, Porta C, Crosignani PG, Ginelli E, Marozzi A. Mutations in the coding region of the FOXL2 gene are not a major cause of idiopathic premature ovarian failure. Mol Hum Reprod 2004; 10 (8) 555-557
• 85 Harris SE, Chand AL, Winship IM, Gersak K, Aittomäki K, Shelling AN. Identification of novel mutations in FOXL2 associated with premature ovarian failure. Mol Hum Reprod 2002; 8 (8) 729-733
• 86 Braem MG, Voorhuis M, van der Schouw YT , et al. Interactions between genetic variants in AMH and AMHR2 may modify age at natural menopause. PLoS ONE 2013; 8 (3) e59819
• 87 Kevenaar ME, Themmen AP, Rivadeneira F , et al. A polymorphism in the AMH type II receptor gene is associated with age at menopause in interaction with parity. Hum Reprod 2007; 22 (9) 2382-2388
• 88 Dupont S, Krust A, Gansmuller A, Dierich A, Chambon P, Mark M. Effect of single and compound knockouts of estrogen receptors alpha (ERalpha) and beta (ERbeta) on mouse reproductive phenotypes. Development 2000; 127 (19) 4277-4291
• 89 Toda K, Takeda K, Okada T , et al. Targeted disruption of the aromatase P450 gene (Cyp19) in mice and their ovarian and uterine responses to 17beta-oestradiol. J Endocrinol 2001; 170 (1) 99-111
• 90 Aittomäki K, Lucena JL, Pakarinen P , et al. Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell 1995; 82 (6) 959-968
• 91 Jiang M, Aittomäki K, Nilsson C , et al. The frequency of an inactivating point mutation (566C—>T) of the human follicle-stimulating hormone receptor gene in four populations using allele-specific hybridization and time-resolved fluorometry. J Clin Endocrinol Metab 1998; 83 (12) 4338-4343
• 92 Doherty E, Pakarinen P, Tiitinen A , et al. A Novel mutation in the FSH receptor inhibiting signal transduction and causing primary ovarian failure. J Clin Endocrinol Metab 2002; 87 (3) 1151-1155
• 93 Achrekar SK, Modi DN, Meherji PK, Patel ZM, Mahale SD. Follicle stimulating hormone receptor gene variants in women with primary and secondary amenorrhea. J Assist Reprod Genet 2010; 27 (6) 317-326
• 94 Zerbetto I, Gromoll J, Luisi S , et al. Follicle-stimulating hormone receptor and DAZL gene polymorphisms do not affect the age of menopause. Fertil Steril 2008; 90 (6) 2264-2268
• 95 La Marca A, Sighinolfi G, Argento C , et al. Polymorphisms in gonadotropin and gonadotropin receptor genes as markers of ovarian reserve and response in in vitro fertilization. Fertil Steril 2013; 99 (4) 970-978 , e1
• 96 He C, Kraft P, Chasman DI , et al. A large-scale candidate gene association study of age at menarche and age at natural menopause. Hum Genet 2010; 128 (5) 515-527
• 97 Spencer KL, Malinowski J, Carty CL , et al. Genetic variation and reproductive timing: African American women from the Population Architecture using Genomics and Epidemiology (PAGE) Study. PLoS ONE 2013; 8 (2) e55258
• 98 Seldin MF, Pasaniuc B, Price AL. New approaches to disease mapping in admixed populations. Nat Rev Genet 2011; 12 (8) 523-528
• 99 Rosenberg NA, Huang L, Jewett EM, Szpiech ZA, Jankovic I, Boehnke M. Genome-wide association studies in diverse populations. Nat Rev Genet 2010; 11 (5) 356-366
• 100 Kim S, Pyun JA, Cha DH, Ko JJ, Kwack K. Epistasis between FSHR and CYP19A1 polymorphisms is associated with premature ovarian failure. Fertil Steril 2011; 95 (8) 2585-2588
• 101 Kim S, Pyun JA, Kang H, Kim J, Cha DH, Kwack K. Epistasis between CYP19A1 and ESR1 polymorphisms is associated with premature ovarian failure. Fertil Steril 2011; 95 (1) 353-356
• 102 Qin Y, Sun M, You L , et al. ESR1, HK3 and BRSK1 gene variants are associated with both age at natural menopause and premature ovarian failure. Orphanet J Rare Dis 2012; 7: 5
• 103 Kim H, Chun S, Gu BS, Ku SY, Kim SH, Kim JG. Relationship between inhibin-α gene polymorphisms and premature ovarian failure in Korean women. Menopause 2011; 18 (11) 1232-1236
• 104 Yoon SH, Choi YM, Hong MA , et al. Inhibin α gene promoter polymorphisms in Korean women with idiopathic premature ovarian failure. Hum Reprod 2012; 27 (6) 1870-1873
• 105 Harris SE, Chand AL, Winship IM , et al. INHA promoter polymorphisms are associated with premature ovarian failure. Mol Hum Reprod 2005; 11 (11) 779-784
• 106 Corre T, Schuettler J, Bione S , et al; Italian Network for the study of Ovarian Dysfunctions. A large-scale association study to assess the impact of known variants of the human INHA gene on premature ovarian failure. Hum Reprod 2009; 24 (8) 2023-2028
• 107 Woad KJ, Pearson SM, Harris SE, Gersak K, Shelling AN. Investigating the association between inhibin alpha gene promoter polymorphisms and premature ovarian failure. Fertil Steril 2009; 91 (1) 62-66
• 108 Yang JJ, Cho LY, Lim YJ , et al. Estrogen receptor-1 genetic polymorphisms for the risk of premature ovarian failure and early menopause. J Womens Health (Larchmt) 2010; 19 (2) 297-304
• 109 Cordts EB, Santos AA, Peluso C, Bianco B, Barbosa CP, Christofolini DM. Risk of premature ovarian failure is associated to the PvuII polymorphism at estrogen receptor gene ESR1. J Assist Reprod Genet 2012; 29 (12) 1421-1425
• 110 M'Rabet N, Moffat R, Helbling S, Kaech A, Zhang H, de Geyter C. The CC-allele of the PvuII polymorphic variant in intron 1 of the α-estrogen receptor gene is significantly more prevalent among infertile women at risk of premature ovarian aging. Fertil Steril 2012; 98 (4) 965-972 , e1–e5
• 111 Fogli A, Gauthier-Barichard F, Schiffmann R , et al. Screening for known mutations in EIF2B genes in a large panel of patients with premature ovarian failure. BMC Womens Health 2004; 4 (1) 8
• 112 Kumar KA, Rao KL, Vedula SV , et al. Screening of the galactose-1-phosphate uridyltransferase gene in Indian women with ovarian failure. Reprod Biomed Online 2005; 11 (4) 444-448
• 113 Jasti S, Warren BD, McGinnis LK, Kinsey WH, Petroff BK, Petroff MG. The autoimmune regulator prevents premature reproductive senescence in female mice. Biol Reprod 2012; 86 (4) 110
• 114 Edson MA, Nalam RL, Clementi C , et al. Granulosa cell-expressed BMPR1A and BMPR1B have unique functions in regulating fertility but act redundantly to suppress ovarian tumor development. Mol Endocrinol 2010; 24 (6) 1251-1266
• 115 Di Giacomo M, Barchi M, Baudat F, Edelmann W, Keeney S, Jasin M. Distinct DNA-damage-dependent and -independent responses drive the loss of oocytes in recombination-defective mouse mutants. Proc Natl Acad Sci U S A 2005; 102 (3) 737-742
• 116 Shen C, Delahanty RJ, Gao YT , et al. Evaluating GWAS-identified SNPs for age at natural menopause among Chinese women. PLoS ONE 2013; 8 (3) e58766
• 117 Stolk L, Perry JR, Chasman DI , et al. Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways. Nat Genet 2012; 44 (3) 260-268
• 118 Pedersen T, Peters H. Proposal for a classification of oocytes and follicles in the mouse ovary. J Reprod Fertil 1968; 17 (3) 555-557
• 119 Lu C, Lin L, Tan H , et al. Fragile X premutation RNA is sufficient to cause primary ovarian insufficiency in mice. Hum Mol Genet 2012; 21 (23) 5039-5047
• 120 Rohr J, Allen EG, Charen K , et al. Anti-Mullerian hormone indicates early ovarian decline in fragile X mental retardation (FMR1) premutation carriers: a preliminary study. Hum Reprod 2008; 23 (5) 1220-1225
• 121 Gleicher N, Weghofer A, Barad DH. A pilot study of premature ovarian senescence: I. Correlation of triple CGG repeats on the FMR1 gene to ovarian reserve parameters FSH and anti-Müllerian hormone. Fertil Steril 2009; 91 (5) 1700-1706
• 122 Spath MA, Feuth TB, Allen EG , et al. Intra-individual stability over time of standardized anti-Mullerian hormone in FMR1 premutation carriers. Hum Reprod 2011; 26 (8) 2185-2191
• 123 Portnoï MF, Aboura A, Tachdjian G , et al. Molecular cytogenetic studies of Xq critical regions in premature ovarian failure patients. Hum Reprod 2006; 21 (9) 2329-2334
• 124 Ceylaner G, Altinkaya SO, Mollamahmutoglu L, Ceylaner S. Genetic abnormalities in Turkish women with premature ovarian failure. Int J Gynaecol Obstet 2010; 110 (2) 122-124
• 125 Jiao X, Qin C, Li J , et al. Cytogenetic analysis of 531 Chinese women with premature ovarian failure. Hum Reprod 2012; 27 (7) 2201-2207
• 126 Rao Kandukuri L, Padmalatha V, Kanakavalli M , et al. Unique case reports associated with ovarian failure: necessity of two intact x chromosomes. Case Rep Genet. 2012; 2012: 640563
• 127 Lakhal B, Braham R, Berguigua R , et al. Cytogenetic analyses of premature ovarian failure using karyotyping and interphase fluorescence in situ hybridization (FISH) in a group of 1000 patients. Clin Genet 2010; 78 (2) 181-185
• 128 Zhang P, Shi Y, Gao X, Wang S, Wang J, Chen ZJ. Clinical analysis of Chinese infertility women with premature ovarian failure. Neuroendocrinol Lett 2007; 28 (5) 580-584
• 129 Lo TK, Lo IF, Chan WK, Tong TM, Lam ST. Chromosomal abnormalities and FMR1 gene premutation in Chinese women with premature menopause. Hong Kong Med J 2005; 11 (4) 243-250
• 130 Yatsenko SA, Rajkovic A. Chromosomal causes of infertility: the story continues. In: Viville S, Sermon K, , eds. Viville & Sermon: Textbook of Human Reproductive Genetics. UK: Cambridge University Press; 2013
• 131 Therman E, Susman B. The similarity of phenotypic effects caused by Xp and Xq deletions in the human female: a hypothesis. Hum Genet 1990; 85 (2) 175-183
• 132 Rossetti F, Rizzolio F, Pramparo T , et al. A susceptibility gene for premature ovarian failure (POF) maps to proximal Xq28. Eur J Hum Genet 2004; 12 (10) 829-834
• 133 Eggermann T, Meschede D, Schüler H , et al. Premature ovarian failure associated with a small terminal Xq deletion: narrowing the POF1 region down to Xq27.2/Xq27.3-qter. Clin Genet 2005; 67 (5) 434-437
• 134 Fimiani G, Laperuta C, Falco G , et al. Heterozygosity mapping by quantitative fluorescent PCR reveals an interstitial deletion in Xq26.2-q28 associated with ovarian dysfunction. Hum Reprod 2006; 21 (2) 529-535
• 135 Marozzi A, Manfredini E, Tibiletti MG , et al. Molecular definition of Xq common-deleted region in patients affected by premature ovarian failure. Hum Genet 2000; 107 (4) 304-311
• 136 Rizzolio F, Bione S, Sala C , et al. Chromosomal rearrangements in Xq and premature ovarian failure: mapping of 25 new cases and review of the literature. Hum Reprod 2006; 21 (6) 1477-1483
• 137 Merhi ZO, Roberts JL, Awonuga AO. A case of 46,X,der(X)t(X;X)(q22.1;p11) Xq22.1—>Xqter in a 12-year-old girl with premature ovarian failure. Gynecol Obstet Invest 2007; 63 (3) 137-139
• 138 Rizzolio F, Sala C, Alboresi S , et al. Epigenetic control of the critical region for premature ovarian failure on autosomal genes translocated to the X chromosome: a hypothesis. Hum Genet 2007; 121 (3-4) 441-450
• 139 Wu MH, Tzeng CC, Kuo PL. Dicentric isochromosome X with premature ovarian failure: report of two cases. J Formos Med Assoc 1993; 92 (9) 848-850
• 140 Fitzgerald PH, Donald RA, McCormick P. Reduced fertility in women with X chromosome abnormality. Clin Genet 1984; 25 (4) 301-309
• 141 Chen CP, Su YN, Lin HH , et al. De novo duplication of Xq22.1→q24 with a disruption of the NXF gene cluster in a mentally retarded woman with short stature and premature ovarian failure. Taiwan J Obstet Gynecol 2011; 50 (3) 339-344
• 142 Guo QS, Qin SY, Zhou SF , et al. Unbalanced translocation in an adult patient with premature ovarian failure and mental retardation detected by spectral karyotyping and array-comparative genomic hybridization. Eur J Clin Invest 2009; 39 (8) 729-737
• 143 Baronchelli S, Villa N, Redaelli S , et al. Investigating the role of X chromosome breakpoints in premature ovarian failure. Mol Cytogenet 2012; 5 (1) 32
• 144 Baronchelli S, Conconi D, Panzeri E , et al. Cytogenetics of premature ovarian failure: an investigation on 269 affected women. J Biomed Biotechnol 2011; 2011: 370195
• 145 Han JY, Shin JH, Han MS, Je GH, Shaffer LG. Microarray detection of a de novo der(X)t(X;11)(q28;p13) in a girl with premature ovarian failure and features of Beckwith-Wiedemann syndrome. J Hum Genet 2006; 51 (7) 641-643
• 146 Dell'edera D, Tinelli A, Capozzi O , et al. Clinical correlation between premature ovarian failure and a chromosomal anomaly in a 22-year-old Caucasian woman: a case report. J Med Case Reports 2012; 6 (1) 368
• 147 Bertini V, Ghirri P, Bicocchi MP, Simi P, Valetto A. Molecular cytogenetic definition of a translocation t(X;15) associated with premature ovarian failure. Fertil Steril 2010; 94 (3) e5-e8
• 148 Giacomozzi C, Gullotta F, Federico G, Colapietro I, Nardone AM, Cianfarani S. Premature ovarian failure, absence of pubic and axillary hair with de novo 46,X,t(X;15)(q24;q26.3). Am J Med Genet A 2010; 152A (5) 1305-1309
• 149 Fusco F, Paciolla M, Chen E , et al. Genetic and molecular analysis of a new unbalanced X;18 rearrangement: localization of the diminished ovarian reserve disease locus in the distal Xq POF1 region. Hum Reprod 2011; 26 (11) 3186-3196
• 150 Misceo D, Rødningen OK, Barøy T , et al. A translocation between Xq21.33 and 22q13.33 causes an intragenic SHANK3 deletion in a woman with Phelan-McDermid syndrome and hypergonadotropic hypogonadism. Am J Med Genet A 2011; 155A (2) 403-408
• 151 Cheng DH, Tan YQ, Di YF, Li LY, Lu GX. Crypt Y chromosome fragment resulting from an X;Y translocation in a patient with premature ovarian failure. Fertil Steril 2009; 92 (2) e3-e6
• 152 Quilter CR, Karcanias AC, Bagga MR , et al. Analysis of X chromosome genomic DNA sequence copy number variation associated with premature ovarian failure (POF). Hum Reprod 2010; 25 (8) 2139-2150
• 153 McGuire MM, Bowden W, Engel NJ, Ahn HW, Kovanci E, Rajkovic A. Genomic analysis using high-resolution single-nucleotide polymorphism arrays reveals novel microdeletions associated with premature ovarian failure. Fertil Steril 2011; 95 (5) 1595-1600
• 154 Aboura A, Dupas C, Tachdjian G , et al. Array comparative genomic hybridization profiling analysis reveals deoxyribonucleic acid copy number variations associated with premature ovarian failure. J Clin Endocrinol Metab 2009; 94 (11) 4540-4546
• 155 Schuh-Huerta SM, Johnson NA, Rosen MP, Sternfeld B, Cedars MI, Reijo Pera RA. Genetic markers of ovarian follicle number and menopause in women of multiple ethnicities. Hum Genet 2012; 131 (11) 1709-1724
• 156 Murray A, Bennett CE, Perry JR , et al; ReproGen Consortium. Common genetic variants are significant risk factors for early menopause: results from the Breakthrough Generations Study. Hum Mol Genet 2011; 20 (1) 186-192
• 157 He C, Murabito JM. Genome-wide association studies of age at menarche and age at natural menopause. Mol Cell Endocrinol 2012; ; [Epub ahead of print]
• 158 Carty CL, Spencer KL, Setiawan VW , et al. Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study. Hum Reprod 2013; 28 (6) 1695-1706
• 159 Chen CT, Fernández-Rhodes L, Brzyski RG , et al. Replication of loci influencing ages at menarche and menopause in Hispanic women: the Women's Health Initiative SHARe Study. Hum Mol Genet 2012; 21 (6) 1419-1432
• 160 He C, Kraft P, Chen C , et al. Genome-wide association studies identify loci associated with age at menarche and age at natural menopause. Nat Genet 2009; 41 (6) 724-728
• 161 Lutzmann M, Grey C, Traver S , et al. MCM8- and MCM9-deficient mice reveal gametogenesis defects and genome instability due to impaired homologous recombination. Mol Cell 2012; 47 (4) 523-534
• 162 Yamaguchi M, Fujimori-Tonou N, Yoshimura Y, Kishi T, Okamoto H, Masai I. Mutation of DNA primase causes extensive apoptosis of retinal neurons through the activation of DNA damage checkpoint and tumor suppressor p53. Development 2008; 135 (7) 1247-1257
• 163 Lehner B, Semple JI, Brown SE, Counsell D, Campbell RD, Sanderson CM. Analysis of a high-throughput yeast two-hybrid system and its use to predict the function of intracellular proteins encoded within the human MHC class III region. Genomics 2004; 83 (1) 153-167
• 164 Singal DP, Li J, Lei K. Genetics of rheumatoid arthritis (RA): two separate regions in the major histocompatibility complex contribute to susceptibility to RA. Immunol Lett 1999; 69 (3) 301-306
• 165 Hashimoto M, Nakamura N, Obayashi H , et al. Genetic contribution of the BAT2 gene microsatellite polymorphism to the age-at-onset of insulin-dependent diabetes mellitus. Hum Genet 1999; 105 (3) 197-199
• 166 Shi J, Long J, Gao YT , et al. Evaluation of genetic susceptibility loci for obesity in Chinese women. Am J Epidemiol 2010; 172 (3) 244-254
• 167 Nieters A, Conde L, Slager SL , et al. PRRC2A and BCL2L11 gene variants influence risk of non-Hodgkin lymphoma: results from the InterLymph consortium. Blood 2012; 120 (23) 4645-4648
• 168 Alazzouzi H, Domingo E, González S , et al. Low levels of microsatellite instability characterize MLH1 and MSH2 HNPCC carriers before tumor diagnosis. Hum Mol Genet 2005; 14 (2) 235-239
• 169 Cummings JR, Cooney RM, Clarke G , et al. The genetics of NOD-like receptors in Crohn's disease. Tissue Antigens 2010; 76 (1) 48-56
• 170 Tadaki H, Saitsu H, Nishimura-Tadaki A , et al. De novo 19q13.42 duplications involving NLRP gene cluster in a patient with systemic-onset juvenile idiopathic arthritis. J Hum Genet 2011; 56 (5) 343-347
• 171 Alvarado-Kristensson M, Rodríguez MJ, Silió V, Valpuesta JM, Carrera AC. SADB phosphorylation of gamma-tubulin regulates centrosome duplication. Nat Cell Biol 2009; 11 (9) 1081-1092
• 172 Lu R, Niida H, Nakanishi M. Human SAD1 kinase is involved in UV-induced DNA damage checkpoint function. J Biol Chem 2004; 279 (30) 31164-31170
• 173 Kishi M, Pan YA, Crump JG, Sanes JR. Mammalian SAD kinases are required for neuronal polarization. Science 2005; 307 (5711) 929-932
• 174 Kim KZ, Shin A, Lee YS, Kim SY, Kim Y, Lee ES. Polymorphisms in adiposity-related genes are associated with age at menarche and menopause in breast cancer patients and healthy women. Hum Reprod 2012; 27 (7) 2193-2200
• 175 Barak Y, Nelson MC, Ong ES , et al. PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell 1999; 4 (4) 585-595
• 176 Cui Y, Miyoshi K, Claudio E , et al. Loss of the peroxisome proliferation-activated receptor gamma (PPARgamma) does not affect mammary development and propensity for tumor formation but leads to reduced fertility. J Biol Chem 2002; 277 (20) 17830-17835
• 177 Long JR, Shu XO, Cai Q , et al. Polymorphisms of the CYP1B1 gene may be associated with the onset of natural menopause in Chinese women. Maturitas 2006; 55 (3) 238-246
• 178 Hefler LA, Grimm C, Heinze G , et al. Estrogen-metabolizing gene polymorphisms and age at natural menopause in Caucasian women. Hum Reprod 2005; 20 (5) 1422-1427
• 179 Sinasac DS, Moriyama M, Jalil MA , et al. Slc25a13-knockout mice harbor metabolic deficits but fail to display hallmarks of adult-onset type II citrullinemia. Mol Cell Biol 2004; 24 (2) 527-536
• 180 Timpl P, Spanagel R, Sillaber I , et al. Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1. Nat Genet 1998; 19 (2) 162-166
• 181 Schwed G, May N, Pechersky Y, Calvi BR. Drosophila minichromosome maintenance 6 is required for chorion gene amplification and genomic replication. Mol Biol Cell 2002; 13 (2) 607-620
• 182 May NR, Thomer M, Murnen KF, Calvi BR. Levels of the origin-binding protein Double parked and its inhibitor Geminin increase in response to replication stress. J Cell Sci 2005; 118 (Pt 18) 4207-4217
• 183 Heard E, Turner J. Function of the sex chromosomes in mammalian fertility. Cold Spring Harb Perspect Biol 2011; 3 (10) a002675
• 184 Bernstein BE, Birney E, Dunham I, Green ED, Gunter C, Snyder M ; ENCODE Project Consortium. An integrated encyclopedia of DNA elements in the human genome. Nature 2012; 489 (7414) 57-74
• 185 Meng FT, Wang YL, Liu J, Zhao J, Liu RY, Zhou JN. ApoE genotypes are associated with age at natural menopause in Chinese females. Age (Dordr) 2012; 34 (4) 1023-1032
• 186 He LN, Recker RR, Deng HW, Dvornyk V. A polymorphism of apolipoprotein E (APOE) gene is associated with age at natural menopause in Caucasian females. Maturitas 2009; 62 (1) 37-41