Skip to main content
SpringerLink
Log in

The Genetics of POI

  • Chapter
Primary Ovarian Insufficiency

Abstract

The vast majority of POI cases throughout the world are spontaneous and idiopathic. Despite expansion of genetic testing, lowered cost, and increased awareness, 90 % of idiopathic, spontaneous POI has no known etiology. The genetics of POI is a growing body of literature and new candidate genes are discovered daily. This chapter presents genetic syndromes of POI and non-syndromic genetic etiologies and describes the unique nature of the X chromosome. If there is a genetic explanation for a woman’s POI, discovering that diagnosis is essential in formulating an individualized prognosis, estimating chance of pregnancy, and learning about future health implications.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 119.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AIRE:

Autoimmune regulator

AMH:

Anti-Mullerian hormone

APECED:

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

APS1:

Autoimmune polyglandular syndrome type I

ATM:

Ataxia telangiectasia mutated

BMP15:

Bone morphogenetic protein 15

BPES:

Blepharophimosis-ptosis-epicanthus inversus syndrome

BRCA1:

Breast cancer susceptibility gene 1

CLPP:

Caseinolytic mitochondrial matrix peptidase proteolytic subunit

CYP17A1:

17α-hydroxylase

CYP19A1:

Aromatase

DACH2:

Dachshund, Drosophila, Homolog Of, 2

DIAPH2:

Diaphanous homolog 2 (Drosophila)

eIF:

Eukaryotic translation initiation factor

ESR:

Estrogen receptor

FMR1:

Fragile X mental retardation 1

FMR2:

Fragile X mental retardation 2

FMRP:

Fragile X mental retardation protein

FOXL2:

Forkhead box transcription factor

FSH:

Follicle-stimulating hormone

FSHR:

FSH receptor

FXS:

Fragile X syndrome

FXTAS:

Fragile X-associated tremor/ataxia syndrome

GALT:

Galactose-1-phosphate uridyltransferase

GDF9:

Growth differentiation factor 9

GnRH:

Gonadotropin-releasing hormone

GnRHR:

GnRH receptor

GPCR:

G-protein-coupled receptor

HARS2:

Histidyl-tRNA synthetase 2, mitochondrial

HCG:

Human chorionic gonadotropin

HSD17B4:

17-Beta-hydroxysteroid dehydrogenase 4, 17-beta-HSD 4

INHA:

Inhibin, alpha

IVF:

In vitro fertilization

LH:

Luteinizing hormone

LHR:

LH receptor

MRI:

Magnetic resonance imaging

OHSS:

Ovarian hyperstimulation syndrome

PEO:

Progressive external ophthalmoplegia

PGRMC1:

Progesterone receptor membrane component 1

POF1:

Premature ovarian failure 1

POF2:

Premature ovarian failure 2

POI:

Primary ovarian insufficiency

POLG:

Polymerase (DNA-directed) gamma

STAR:

Steroidogenic acute regulatory protein

TGFβ:

Transforming growth factor β

TSH:

Thyroid-stimulating hormone

USP9X:

Ubiquitin-specific protease 9

USP9X:

Ubiquitin-specific protease 9

WRN:

Werner

XPNPEP2:

X-Prolyl aminopeptidase 2

ZFX:

Zinc finger X

ZFX:

Zinc finger protein, X-linked

References

  1. Grindler NM, Allsworth JE, Macones GA, Kannan K, Roehl KA, Cooper AR. Persistent organic pollutants and early menopause in U.S. women. PLoS One. 2015;10(1), e0116057.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  2. Ovarian Kaleidoscope [Internet]. [cited January 11 2015]. Available from: http://okdb.appliedbioinfo.net.

  3. Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl J Med. 2009;360(6):606–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. van Kasteren YM, Hundscheid RD, Smits AP, Cremers FP, van Zonneveld P, Braat DD. Familial idiopathic premature ovarian failure: an overrated and underestimated genetic disease? Hum Reprod. 1999;14(10):2455–9.

    Article  PubMed  Google Scholar 

  5. De Vos M, Devroey P, Fauser BCJM. Primary ovarian insufficiency. Lancet. 2010;376(9744):911–21.

    Article  PubMed  Google Scholar 

  6. Rebar RW. Premature ovarian failure. Obstet Gynecol. 2009;113(6):1355–63.

    Article  PubMed  Google Scholar 

  7. Baker VL. Primary ovarian insufficiency in the adolescent. Curr Opin Obstet Gynecol. 2013;25(5):375–81.

    Article  PubMed  Google Scholar 

  8. Reindollar RH, Byrd JR, McDonough PG. Delayed sexual development: a study of 252 patients. Am J Obstet Gynecol. 1981;140(4):371–80.

    CAS  PubMed  Google Scholar 

  9. Rajangam S, Nanjappa L. Cytogenetic studies in amenorrhea. Saudi Med J. 2007;28(2):187–92.

    PubMed  Google Scholar 

  10. Baber RJ, Kwik M. Primary ovarian insufficiency. Curr Obstet Gynecol Rep. 2014;3:223–31.

    Article  Google Scholar 

  11. Cordts EB, Christofolini DM, Dos Santos AA, Bianco B, Barbosa CP. Genetic aspects of premature ovarian failure: a literature review. Arch Gynecol Obstet. 2011;283(3):635–43.

    Article  PubMed  Google Scholar 

  12. Simpson JL. Genetic and phenotypic heterogeneity in ovarian failure: overview of selected candidate genes. Ann N Y Acad Sci. 2008;1135:146–54.

    Article  PubMed  Google Scholar 

  13. Fritz MA, Speroff L. Clinical gynecologic endocrinology and infertility. 8th ed. Philadelphia: Lippincott Williams & Wilkins; 2011.

    Google Scholar 

  14. Persani L, Rossetti R, Cacciatore C. Genes involved in human premature ovarian failure. J Mol Endocrinol. 2010;45(5):257–79.

    Article  CAS  PubMed  Google Scholar 

  15. Fortuno C, Labarta E. Genetics of primary ovarian insufficiency: a review. J Assist Reprod Genet. 2014;31(12):1573–85.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Reindollar RH. Turner syndrome: contemporary thoughts and reproductive issues. Semin Reprod Med. 2011;29(4):342–52.

    Article  PubMed  Google Scholar 

  17. Hewitt JK, Jayasinghe Y, Amor DJ, Gillam LH, Warne GL, Grover S, et al. Fertility in Turner syndrome. Clin Endocrinol. 2013;79(5):606–14.

    Google Scholar 

  18. Hadnott TN, Gould HN, Gharib AM, Bondy CA. Outcomes of spontaneous and assisted pregnancies in Turner syndrome: the U.S. National Institutes of Health experience. Fertil Steril. 2011;95(7):2251–6.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Ranke MB, Saenger P. Turner’s syndrome. Lancet. 2001;358(9278):309–14.

    Article  CAS  PubMed  Google Scholar 

  20. Bondy CA. New issues in the diagnosis and management of Turner syndrome. Rev Endocr Metab Disord. 2005;6(4):269–80.

    Article  PubMed  Google Scholar 

  21. Russell LM, Strike P, Browne CE, Jacobs PA. X chromosome loss and ageing. Cytogenet Genome Res. 2007;116(3):181–5.

    Article  CAS  PubMed  Google Scholar 

  22. Practice Committee of American Society For Reproductive Medicine. Increased maternal cardiovascular mortality associated with pregnancy in women with Turner syndrome. Fertil Steril. 2012;97(2):282–4.

    Google Scholar 

  23. Bondy CA. Aortic dissection in Turner syndrome. Curr Opin Cardiol. 2008;23(6):519–26.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Uhlenhaut NH, Treier M. Foxl2 function in ovarian development. Mol Genet Metab. 2006;88(3):225–34.

    Article  CAS  PubMed  Google Scholar 

  25. Dixit H, Rao L, Padmalatha V, Raseswari T, Kapu AK, Panda B, et al. Genes governing premature ovarian failure. Reprod Biomed Online. 2010;20(6):724–40.

    Article  CAS  PubMed  Google Scholar 

  26. Georges A, Auguste A, Bessiere L, Vanet A, Todeschini AL, Veitia RA. FOXL2: a central transcription factor of the ovary. J Mol Endocrinol. 2014;52(1):R17–33.

    Article  CAS  PubMed  Google Scholar 

  27. Kim JH, Bae J. Differential apoptotic and proliferative activities of wild-type FOXL2 and blepharophimosis-ptosis-epicanthus inversus syndrome (BPES)-associated mutant FOXL2 proteins. J Reprod Dev. 2014;60(1):14–20.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Siewert AL, Stein Q, Flanagan J, Hansen KA. Blepharophimosis-ptosis-epicanthus inversus syndrome and hypergonadotropic hypogonadism. Fertility and Sterility. 2008;90(5):2016.e11–2.

    Article  Google Scholar 

  29. Crisponi L, Deiana M, Loi A, Chiappe F, Uda M, Amati P, et al. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome. Nat Genet. 2001;27(2):159–66.

    Article  CAS  PubMed  Google Scholar 

  30. Roth LW, Alvero R. Pregnancy in a woman with premature ovarian insufficiency associated with blepharophimosis, ptosis, epicanthus inversus syndrome type I. A case report. J Reprod Med. 2014;59(1-2):87–9.

    PubMed  Google Scholar 

  31. van Erven B, Gubbels CS, van Golde RJ, Dunselman GA, Derhaag JG, de Wert G, et al. Fertility preservation in female classic galactosemia patients. Orphanet J Rare Dis. 2013;8:107.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Tyfield L, Reichardt J, Fridovich-Keil J, Croke DT, Elsas 2nd LJ, Strobl W, et al. Classical galactosemia and mutations at the galactose-1-phosphate uridyl transferase (GALT) gene. Hum Mutat. 1999;13(6):417–30.

    Article  CAS  PubMed  Google Scholar 

  33. Sanders RD, Spencer JB, Epstein MP, Pollak SV, Vardhana PA, Lustbader JW, et al. Biomarkers of ovarian function in girls and women with classic galactosemia. Fertil Steril. 2009;92(1):344–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Anheim M, Tranchant C, Koenig M. The autosomal recessive cerebellar ataxias. N Engl J Med. 2012;366(7):636–46.

    Article  CAS  PubMed  Google Scholar 

  35. Caballero PE, Candela MS, Alvarez CI, Tejerina AA. Chronic progressive external ophthalmoplegia: a report of 6 cases and a review of the literature. Neurologist. 2007;13(1):33–6.

    Article  PubMed  Google Scholar 

  36. Luoma P, Melberg A, Rinne JO, Kaukonen JA, Nupponen NN, Chalmers RM, et al. Parkinsonism, premature menopause, and mitochondrial DNA polymerase γ mutations: clinical and molecular genetic study. Lancet. 2004;364(9437):875–82.

    Article  CAS  PubMed  Google Scholar 

  37. Pagnamenta AT, Taanman JW, Wilson CJ, Anderson NE, Marotta R, Duncan AJ, et al. Dominant inheritance of premature ovarian failure associated with mutant mitochondrial DNA polymerase gamma. Hum Reprod. 2006;21(10):2467–73.

    Article  CAS  PubMed  Google Scholar 

  38. Pierce SB, Gersak K, Michaelson-Cohen R, Walsh T, Lee MK, Malach D, et al. Mutations in LARS2, encoding mitochondrial leucyl-tRNA synthetase, lead to premature ovarian failure and hearing loss in Perrault syndrome. Am J Hum Genet. 2013;92(4):614–20.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Ameen KH, Pinninti R. A rare cause for primary amenorrhea: Sporadic perrault syndrome. Ind J Endocrinol Metabol. 2012;16(5):843–5.

    Article  Google Scholar 

  40. Kim MJ, Kim SJ, Kim J, Chae H, Kim M, Kim Y. Genotype and phenotype heterogeneity in perrault syndrome. J Pediatr Adolesc Gynecol. 2013;26(1):e25–7.

    Article  PubMed  Google Scholar 

  41. Eisenbarth GS, Gottlieb PA. Autoimmune polyendocrine syndromes. N Engl J Med. 2004;350(20):2068–79.

    Article  CAS  PubMed  Google Scholar 

  42. Fierabracci A, Bizzarri C, Palma A, Milillo A, Bellacchio E, Cappa M. A novel heterozygous mutation of the AIRE gene in a patient with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED). Gene. 2012;511(1):113–7.

    Article  CAS  PubMed  Google Scholar 

  43. Perheentupa J. Autoimmune polyendocrinopathy--candidiasis--ectodermal dystrophy (APECED). Horm Metab Res. 1996;28(7):353–6.

    Article  CAS  PubMed  Google Scholar 

  44. Chen S, Sawicka J, Betterle C, Powell M, Prentice L, Volpato M, et al. Autoantibodies to steroidogenic enzymes in autoimmune polyglandular syndrome, Addison's disease, and premature ovarian failure. J Clin Endocrinol Metab. 1996;81(5):1871–6.

    CAS  PubMed  Google Scholar 

  45. Kauffman RP, Castracane VD. Premature ovarian failure associated with autoimmune polyglandular syndrome: pathophysiological mechanisms and future fertility. J Womens Health. 2003;12(5):513–20.

    Article  Google Scholar 

  46. Schiffmann R, Tedeschi G, Kinkel RP, Trapp BD, Frank JA, Kaneski CR, et al. Leukodystrophy in patients with ovarian dysgenesis. Ann Neurol. 1997;41(5):654–61.

    Article  CAS  PubMed  Google Scholar 

  47. van der Knaap MS, Pronk JC, Scheper GC. Vanishing white matter disease. Lancet Neurol. 2006;5(5):413–23.

    Article  PubMed  Google Scholar 

  48. Fogli A, Rodriguez D, Eymard-Pierre E, Bouhour F, Labauge P, Meaney BF, et al. Ovarian failure related to eukaryotic initiation factor 2B mutations. Am J Hum Genet. 2003;72(6):1544–50.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Gaudiano C, Di Perri C, Scali O, Rufa A, Battisti C, De Stefano N, et al. A case of ovarioleukodystrophy without eIF2B mutations. J Neurol Sci. 2008;268(1-2):183–6.

    Article  CAS  PubMed  Google Scholar 

  50. Kaku U, Kameyama K, Izawa M, Yamada M, Miyamoto J, Suzuki T, et al. Ovarian histological findings in an adult patient with the steroidogenic acute regulatory protein (StAR) deficiency reveal the impairment of steroidogenesis by lipoid deposition. Endocr J. 2008;55(6):1043–9.

    Article  PubMed  Google Scholar 

  51. Lin D, Sugawara T, Strauss 3rd JF, Clark BJ, Stocco DM, Saenger P, et al. Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis. Science. 1995;267(5205):1828–31.

    Article  CAS  PubMed  Google Scholar 

  52. Lin L, Ercan O, Raza J, Burren CP, Creighton SM, Auchus RJ, et al. Variable phenotypes associated with aromatase (CYP19) insufficiency in humans. J Clin Endocrinol Metab. 2007;92(3):982–90.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Bulun SE. Aromatase and estrogen receptor alpha deficiency. Fertil Steril. 2014;101(2):323–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Hasty P, Campisi J, Hoeijmakers J, van Steeg H, Vijg J. Aging and genome maintenance: lessons from the mouse? Science. 2003;299(5611):1355–9.

    Article  CAS  PubMed  Google Scholar 

  55. Hisama FM, Kubisch C, Martin GM, Oshima J. Clinical utility gene card for: Werner syndrome. Eur J Hum Genet. 2015;23(6).

    Google Scholar 

  56. Goto M. Hierarchical deterioration of body systems in Werner's syndrome: implications for normal ageing. Mech Ageing Dev. 1997;98(3):239–54.

    Article  CAS  PubMed  Google Scholar 

  57. Muftuoglu M, Oshima J, von Kobbe C, Cheng WH, Leistritz DF, Bohr VA. The clinical characteristics of Werner syndrome: molecular and biochemical diagnosis. Hum Genet. 2008;124(4):369–77.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Friedrich K, Lee L, Leistritz DF, Nurnberg G, Saha B, Hisama FM, et al. WRN mutations in Werner syndrome patients: genomic rearrangements, unusual intronic mutations and ethnic-specific alterations. Hum Genet. 2010;128(1):103–11.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  59. Goldstein S, Murano S, Shmookler Reis RJ. Werner syndrome: a molecular genetic hypothesis. J Gerontol. 1990;45(1):B3–8.

    Article  CAS  PubMed  Google Scholar 

  60. Murakami M. Pregnancy complicated by Werner’s syndrome. BJOG. 2003;110(6):635–6.

    Article  PubMed  Google Scholar 

  61. D'Andrea AD. Susceptibility pathways in Fanconi's anemia and breast cancer. N Engl J Med. 2010;362(20):1909–19.

    Article  PubMed Central  PubMed  Google Scholar 

  62. Kupfer GM. Fanconi anemia: a signal transduction and DNA repair pathway. Yale J Biol Med. 2013;86(4):491–7.

    PubMed Central  CAS  PubMed  Google Scholar 

  63. Alter BP, Frissora CL, Halperin DS, Freedman MH, Chitkara U, Alvarez E, et al. Fanconi’s anaemia and pregnancy. Br J Haematol. 1991;77(3):410–8.

    Article  CAS  PubMed  Google Scholar 

  64. Sklavos MM, Giri N, Stratton P, Alter BP, Pinto LA. Anti-Mullerian hormone deficiency in females with Fanconi anemia. J Clin Endocrinol Metab. 2014;99(5):1608–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  65. Sullivan SD, Welt C, Sherman S. FMR1 and the continuum of primary ovarian insufficiency. Semin Reprod Med. 2011;29(4):299–307.

    Article  PubMed  Google Scholar 

  66. Wittenberger MD, Hagerman RJ, Sherman SL, McConkie-Rosell A, Welt CK, Rebar RW, et al. The FMR1 premutation and reproduction. Fertil Steril. 2007;87(3):456–65.

    Article  CAS  PubMed  Google Scholar 

  67. Peprah E. Understanding decreased fertility in women carriers of the FMR1 premutation: a possible mechanism for Fragile X-Associated Primary Ovarian Insufficiency (FXPOI). Reprod Health. 2014;11:67.

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  68. Sullivan AK, Marcus M, Epstein MP, Allen EG, Anido AE, Paquin JJ, et al. Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod. 2005;20(2):402–12.

    Article  CAS  PubMed  Google Scholar 

  69. Ennis S, Ward D, Murray A. Nonlinear association between CGG repeat number and age of menopause in FMR1 premutation carriers. Eur J Hum Genet. 2006;14(2):253–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  70. Murray A, Webb J, Dennis N, Conway G, Morton N. Microdeletions in FMR2 may be a significant cause of premature ovarian failure. J Med Genet. 1999;36(10):767–70.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Welt CK, Smith PC, Taylor AE. Evidence of early ovarian aging in fragile X premutation carriers. J Clin Endocrinol Metab. 2004;89(9):4569–74.

    Article  CAS  PubMed  Google Scholar 

  72. van Kasteren YM, Schoemaker J. Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum Reprod Update. 1999;5(5):483–92.

    Article  PubMed  Google Scholar 

  73. Szabat M, Johnson JD. Modulation of beta-cell fate and function by TGFbeta ligands: a superfamily with many powers. Endocrinology. 2013;154(11):3965–9.

    Article  CAS  PubMed  Google Scholar 

  74. Shimasaki S, Moore RK, Otsuka F, Erickson GF. The bone morphogenetic protein system in mammalian reproduction. Endocr Rev. 2004;25(1):72–101.

    Article  CAS  PubMed  Google Scholar 

  75. Di Pasquale E, Beck-Peccoz P, Persani L. Hypergonadotropic ovarian failure associated with an inherited mutation of human bone morphogenetic protein-15 (BMP15) gene. Am J Hum Genet. 2004;75(1):106–11.

    Article  PubMed Central  PubMed  Google Scholar 

  76. Persani L, Rossetti R, Di Pasquale E, Cacciatore C, Fabre S. The fundamental role of bone morphogenetic protein 15 in ovarian function and its involvement in female fertility disorders. Hum Reprod Update. 2014;20(6):869–83.

    Article  PubMed  Google Scholar 

  77. Galloway SM, Gregan SM, Wilson T, McNatty KP, Juengel JL, Ritvos O, et al. Bmp15 mutations and ovarian function. Mol Cell Endocrinol. 2002;191(1):15–8.

    Article  CAS  PubMed  Google Scholar 

  78. Yan C, Wang P, DeMayo J, DeMayo FJ, Elvin JA, Carino C, et al. Synergistic roles of bone morphogenetic protein 15 and growth differentiation factor 9 in ovarian function. Mol Endocrinol. 2001;15(6):854–66.

    Article  CAS  PubMed  Google Scholar 

  79. Dixit H, Rao LK, Padmalatha V, Kanakavalli M, Deenadayal M, Gupta N, et al. Mutational screening of the coding region of growth differentiation factor 9 gene in Indian women with ovarian failure. Menopause. 2005;12(6):749–54.

    Article  PubMed  Google Scholar 

  80. Kingsley DM. The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev. 1994;8(2):133–46.

    Article  CAS  PubMed  Google Scholar 

  81. Chand AL, Harrison CA, Shelling AN. Inhibin and premature ovarian failure. Hum Reprod Update. 2010;16(1):39–50.

    Article  CAS  PubMed  Google Scholar 

  82. Themmen AP. An update of the pathophysiology of human gonadotrophin subunit and receptor gene mutations and polymorphisms. Reproduction. 2005;130(3):263–74.

    Article  CAS  PubMed  Google Scholar 

  83. Aittomaki K, Lucena JL, Pakarinen P, Sistonen P, Tapanainen J, Gromoll J, et al. Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure. Cell. 1995;82(6):959–68.

    Article  CAS  PubMed  Google Scholar 

  84. Jiang M, Aittomaki K, Nilsson C, Pakarinen P, Iitia A, Torresani T, 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):4338–43.

    CAS  PubMed  Google Scholar 

  85. Lussiana C, Guani B, Mari C, Restagno G, Massobrio M, Revelli A. Mutations and polymorphisms of the FSH receptor (FSHR) gene: clinical implications in female fecundity and molecular biology of FSHR protein and gene. Obstet Gynecol Surv. 2008;63(12):785–95.

    Article  PubMed  Google Scholar 

  86. Woad KJ, Prendergast D, Winship IM, Shelling AN. FSH receptor gene variants are rarely associated with premature ovarian failure. Reprod Biomed Online. 2013;26(4):396–9.

    Article  CAS  PubMed  Google Scholar 

  87. Binder H, Strick R, Zaherdoust O, Dittrich R, Hamori M, Beckmann MW, et al. Assessment of FSHR variants and antimullerian hormone in infertility patients with a reduced ovarian response to gonadotropin stimulation. Fertil Steril. 2012;97(5):1169–75. e1.

    Article  CAS  PubMed  Google Scholar 

  88. Ghadami M, El-Demerdash E, Salama SA, Binhazim AA, Archibong AE, Chen X, et al. Toward gene therapy of premature ovarian failure: intraovarian injection of adenovirus expressing human FSH receptor restores folliculogenesis in FSHR(-/-) FORKO mice. Mol Hum Reprod. 2010;16(4):241–50.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  89. Binder H, Dittrich R, Hager I, Muller A, Oeser S, Beckmann MW, et al. Association of FSH receptor and CYP19A1 gene variations with sterility and ovarian hyperstimulation syndrome. Reproduction. 2008;135(1):107–16.

    Article  CAS  PubMed  Google Scholar 

  90. Batista MC, Duarte Ede F, Borba MD, Zingler E, Mangussi-Gomes J, dos Santos BT, et al. Trp28Arg/Ile35Thr LHB gene variants are associated with elevated testosterone levels in women with polycystic ovary syndrome. Gene. 2014;550(1):68–73.

    Article  CAS  PubMed  Google Scholar 

  91. Latronico AC, Arnhold IJ. Inactivating mutations of the human luteinizing hormone receptor in both sexes. Semin Reprod Med. 2012;30(5):382–6.

    Article  CAS  PubMed  Google Scholar 

  92. Chevrier L, Guimiot F, de Roux N. GnRH receptor mutations in isolated gonadotropic deficiency. Mol Cell Endocrinol. 2011;346(1-2):21–8.

    Article  CAS  PubMed  Google Scholar 

  93. Layman LC. Mutations in human gonadotropin genes and their physiologic significance in puberty and reproduction. Fertil Steril. 1999;71(2):201–18.

    Article  CAS  PubMed  Google Scholar 

  94. de Roux N, Young J, Misrahi M, Genet R, Chanson P, Schaison G, et al. A family with hypogonadotropic hypogonadism and mutations in the gonadotropin-releasing hormone receptor. N Engl J Med. 1997;337(22):1597–602.

    Article  PubMed  Google Scholar 

  95. Weel AE, Uitterlinden AG, Westendorp IC, Burger H, Schuit SC, Hofman A, et al. Estrogen receptor polymorphism predicts the onset of natural and surgical menopause. J Clin Endocrinol Metab. 1999;84(9):3146–50.

    CAS  PubMed  Google Scholar 

  96. Yoon SH, Choi YM, Hong MA, Lee GH, Kim JJ, Im HJ, et al. Estrogen receptor {alpha} gene polymorphisms in patients with idiopathic premature ovarian failure. Hum Reprod. 2010;25(1):283–7.

    Article  CAS  PubMed  Google Scholar 

  97. Bretherick KL, Hanna CW, Currie LM, Fluker MR, Hammond GL, Robinson WP. Estrogen receptor alpha gene polymorphisms are associated with idiopathic premature ovarian failure. Fertil Steril. 2008;89(2):318–24.

    Article  CAS  PubMed  Google Scholar 

  98. 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 alpha-estrogen receptor gene is significantly more prevalent among infertile women at risk of premature ovarian aging. Fertil Steril. 2012;98(4):965–72.e1–5.

    Google Scholar 

  99. Mansouri MR, Schuster J, Badhai J, Stattin EL, Losel R, Wehling M, et al. Alterations in the expression, structure and function of progesterone receptor membrane component-1 (PGRMC1) in premature ovarian failure. Hum Mol Genet. 2008;17(23):3776–83.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  100. Zhao G, Zhou X, Fang T, Hou Y, Hu Y. Hyaluronic acid promotes the expression of progesterone receptor membrane component 1 via epigenetic silencing of miR-139-5p in human and rat granulosa cells. Biol Reprod. 2014;91(5):116.

    Article  PubMed  CAS  Google Scholar 

  101. Wang ET, Pisarska MD, Bresee C, Chen YD, Lester J, Afshar Y, et al. BRCA1 germline mutations may be associated with reduced ovarian reserve. Fertil Steril. 2014;102(6):1723–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  102. Oktay K, Kim JY, Barad D, Babayev SN. Association of BRCA1 mutations with occult primary ovarian insufficiency: a possible explanation for the link between infertility and breast/ovarian cancer risks. J Clin Oncol. 2010;28(2):240–4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  103. Titus S, Li F, Stobezki R, Akula K, Unsal E, Jeong K, et al. Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans. Sci Transl Med. 2013;5(172):172ra21.

    Article  PubMed  CAS  Google Scholar 

  104. Toniolo D, Rizzolio F. X chromosome and ovarian failure. Semin Reprod Med. 2007;25(4):264–71.

    Article  CAS  PubMed  Google Scholar 

  105. Simpson JL, Rajkovic A. Ovarian differentiation and gonadal failure. Am J Med Genet. 1999;89(4):186–200.

    Article  CAS  PubMed  Google Scholar 

  106. Rizzolio F, Bione S, Sala C, Goegan M, Gentile M, Gregato G, 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):1477–83.

    Article  CAS  PubMed  Google Scholar 

  107. Jones MH, Furlong RA, Burkin H, Chalmers IJ, Brown GM, Khwaja O, et al. The Drosophila developmental gene fat facets has a human homologue in Xp11.4 which escapes X-inactivation and has related sequences on Yq11.2. Hum Mol Genet. 1996;5(11):1695–701.

    Article  CAS  PubMed  Google Scholar 

  108. Luoh SW, Bain PA, Polakiewicz RD, Goodheart ML, Gardner H, Jaenisch R, et al. Zfx mutation results in small animal size and reduced germ cell number in male and female mice. Development. 1997;124(11):2275–84.

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Washington University, 660 South Euclid Avenue, Campus Box 8513, St. Louis, MO, 63110, USA

    Violet Klenov MD & Amber R. Cooper MD, MSCI

Authors
  1. Violet Klenov MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amber R. Cooper MD, MSCI
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Amber R. Cooper MD, MSCI .

Editor information

Editors and Affiliations

  1. Obstetrics and Gynecology, University of Colorado, Aurora, Colorado, USA

    Nanette F. Santoro

  2. Obstetrics and Gynecology, Washington University, St. Louis, Missouri, USA

    Amber R. Cooper

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Klenov, V., Cooper, A.R. (2016). The Genetics of POI. In: Santoro, N., Cooper, A. (eds) Primary Ovarian Insufficiency. Springer, Cham. https://doi.org/10.1007/978-3-319-22491-6_4

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-22491-6_4

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-22490-9

  • Online ISBN: 978-3-319-22491-6

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation