X Chromosome and Ovarian Failure

ABSTRACT

Genes for reproduction are enriched on the sex chromosomes and they may be involved in the many forms of X- or Y-linked infertility. Here we review the X-linked disorders of ovulation and we show that despite the relatively frequent observation of X chromosome rearrangements in women with ovarian dysgenesis or ovarian failure, the search for X-linked genes has not yet been very fruitful: only two genes have been demonstrated definitively, BMP15 and FMR1. However, the size of the rearrangements and the characteristics of some of the genes suggest that many of the X-linked genes only rarely may be causative and more frequently they may represent risk factors for premature ovarian failure (POF) and will have to be identified by specific approaches. Moreover, recent data seem to suggest a structural and novel role for the X chromosome in some of the POF rearrangements, and also that X-linked POF is not always dependent from the presence of X-linked genes.

X chromosome monosomy - premature ovarian failure - infertility

REFERENCES

• 1 Charlesworth D, Charlesworth B, Marais G. Steps in the evolution of heteromorphic sex chromosomes.  Heredity. 2005;  95 118-128
• 2 Lahn B T, Pearson N M, Jegalian K. The human Y chromosome, in the light of evolution.  Nat Rev Genet. 2001;  2 207-216
• 3 Bachtrog D. A dynamic view of sex chromosome evolution.  Curr Opin Genet Dev. 2006;  16 578-585
• 4 Lahn B T, Page D C. Four evolutionary strata on the human X chromosome.  Science. 1999;  286 964-967
• 5 Vallender E J, Lahn B T. How mammalian sex chromosomes acquired their peculiar gene content.  Bioessays. 2004;  26 159-169
• 6 Vicoso B, Charlesworth B. Evolution on the X chromosome: unusual patterns and processes.  Nat Rev Genet. 2006;  7 645-653
• 7 Graves J A. Sex chromosome specialization and degeneration in mammals.  Cell. 2006;  124 901-914
• 8 Clerc P, Avner P. Random X-chromosome inactivation: skewing lessons for mice and men.  Curr Opin Genet Dev. 2006;  16 246-253
• 9 Carrel L, Willard H F. X-inactivation profile reveals extensive variability in X-linked gene expression in females.  Nature. 2005;  434 400-404
• 10 Khil P P, Smirnova N A, Romanienko P J, Camerini-Otero R D. The mouse X chromosome is enriched for sex-biased genes not subject to selection by meiotic sex chromosome inactivation.  Nat Genet. 2004;  36 642-646
• 11 Zinn A R, Ross J L. Turner syndrome and haploinsufficiency.  Curr Opin Genet Dev. 1998;  8 322-327
• 12 Rao E, Weiss B, Fukami M et al.. Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome.  Nat Genet. 1997;  16 54-63
• 13 Belin V, Cusin V, Viot G et al.. SHOX mutations in dyschondrosteosis (Leri-Weill syndrome).  Nat Genet. 1998;  19 67-69
• 14 Shears D J, Vassal H J, Goodman F R et al.. Mutation and deletion of the pseudoautosomal gene SHOX cause Leri-Weill dyschondrosteosis.  Nat Genet. 1998;  19 70-73
• 15 Clement-Jones M, Schiller S, Rao E et al.. The short stature homeobox gene SHOX is involved in skeletal abnormalities in Turner syndrome.  Hum Mol Genet. 2000;  9 695-702
• 16 Gartler S M, Andina R, Gant N. Ontogeny of X-chromosome inactivation in the female germ line.  Exp Cell Res. 1975;  91 454-457
• 17 Speed R M. The possible role of meiotic pairing anomalies in the atresia of human fetal oocytes.  Hum Genet. 1988;  78 260-266
• 18 Coulam C B, Adamson S C, Annegers J F. Incidence of premature ovarian failure.  Obstet Gynecol. 1986;  67 604-606
• 19 Goswami D, Conway G. Premature ovarian failure.  Hum Reprod Update. 2005;  11 391-410
• 20 Zinn A R, Tonk V S, Chen Z et al.. Evidence for a Turner syndrome locus or loci at Xp11.2-p22.1  Am J Hum Genet. 1998;  63 1757-1766
• 21 Ogata T, Muroya K, Matsuo N et al.. Turner syndrome and Xp deletions: clinical and molecular studies in 47 patients.  J Clin Endocrinol Metab. 2001;  86 5498-5508
• 22 Lachlan K L, Youings S, Costa T, Jacobs P A, Thomas N S. A clinical and molecular study of 26 females with Xp deletions with special emphasis on inherited deletions.  Hum Genet. 2006;  118 640-651
• 23 Simpson J L, Rajkovic A. Ovarian differentiation and gonadal failure.  Am J Med Genet. 1999;  89 186-200
• 24 Ogata T, Matsuo N. Turner syndrome and female sex chromosome aberrations: deduction of the principal factors involved in the development of clinical features.  Hum Genet. 1995;  95 607-629
• 25 Maraschio P, Tupler R, Barbierato L et al.. An analysis of Xq deletions.  Hum Genet. 1996;  97 375-381
• 26 Marozzi A, Manfredini E, Tibiletti M G et al.. Molecular definition of Xq common-deleted region in patients affected by premature ovarian failure.  Hum Genet. 2000;  107 304-311
• 27 Cremers F P, van de Pol D J, Diergaarde P J et al.. Physical fine mapping of the choroideremia locus using Xq21 deletions associated with complex syndromes.  Genomics. 1989;  4 41-46
• 28 Krauss C M, Turksoy R N, Atkins L et al.. Familial premature ovarian failure due to an interstitial deletion of the long arm of the X chromosome.  N Engl J Med. 1987;  317 125-131
• 29 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 1477-1483
• 30 Schwartz C, Fitch N, Phelan M C, Richer C L, Stevenson R. Two sisters with a distal deletion at the Xq26/Xq27 interface: DNA studies indicate that the gene locus for factor IX is present.  Hum Genet. 1987;  76 54-57
• 31 Trunca C, Therman E, Rosenwaks Z. The phenotypic effects of small, distal Xq deletions.  Hum Genet. 1984;  68 87-89
• 32 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;  12 829-834
• 33 Eggermann T, Meschede D, Schuler 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;  67 434-437
• 34 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;  21 529-535
• 35 Portnoi M F, Aboura A, Tachdjian G et al.. Molecular cytogenetic studies of Xq critical regions in premature ovarian failure patients.  Hum Reprod. 2006;  21 2329-2334
• 36 Luborsky J L, Meyer P, Sowers M F, Gold E B, Santoro N. Premature menopause in a multi-ethnic population study of the menopause transition.  Hum Reprod. 2003;  18 199-206
• 37 Moncayo R, Moncayo H E. Autoimmunity and the ovary.  Immunol Today. 1992;  13 255-258
• 38 Luborsky J. Ovarian autoimmune disease and ovarian autoantibodies.  J Womens Health Gend Based Med. 2002;  11 585-599
• 39 Aittomaki K, Lucena J L, Pakarinen P et al.. Mutation in the follicle-stimulating hormone receptor gene causes hereditary hypergonadotropic ovarian failure.  Cell. 1995;  82 959-968
• 40 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;  75 106-111
• 41 Crisponi L, Deiana M, Loi A et al.. The putative forkhead transcription factor FOXL2 is mutated in blepharophimosis/ptosis/epicanthus inversus syndrome.  Nat Genet. 2001;  27 159-166
• 42 Fogli A, Rodriguez D, Eymard-Pierre E et al.. Ovarian failure related to eukaryotic initiation factor 2B mutations.  Am J Hum Genet. 2003;  72 1544-1550
• 43 Laml T, Preyer O, Umek W, Hengstschlager M, Hanzal H. Genetic disorders in premature ovarian failure.  Hum Reprod Update. 2002;  8 483-491
• 44 Therman E, Susman B. The similarity of phenotypic effects caused by Xp and Xq deletions in the human female: a hypothesis.  Hum Genet. 1990;  85 175-183
• 45 Therman E, Laxova R, Susman B. The critical region on the human Xq.  Hum Genet. 1990;  85 455-461
• 46 Schlessinger D, Herrera L, Crisponi L et al.. Genes and translocations involved in POF.  Am J Med Genet. 2002;  111 328-333
• 47 Turner J M, Mahadevaiah S K, Fernandez-Capetillo O et al.. Silencing of unsynapsed meiotic chromosomes in the mouse.  Nat Genet. 2005;  37 41-47
• 48 Sala C, Arrigo G, Torri G et al.. Eleven X chromosome breakpoints associated with premature ovarian failure (POF) map to a 15-Mb YAC contig spanning Xq21.  Genomics. 1997;  40 123-131
• 49 Mumm S, Herrera L, Waeltz P W et al.. X/autosomal translocations in the Xq critical region associated with premature ovarian failure fall within and outside genes.  Genomics. 2001;  76 30-36
• 50 Prueitt R L, Chen H, Barnes R I, Zinn A R. Most X;autosome translocations associated with premature ovarian failure do not interrupt X-linked genes.  Cytogenet Genome Res. 2002;  97 32-38
• 51 Bione S, Sala C, Manzini C et al.. A human homologue of the Drosophila melanogaster diaphanous gene is disrupted in a patient with premature ovarian failure: evidence for conserved function in oogenesis and implications for human sterility.  Am J Hum Genet. 1998;  62 533-541
• 52 Prueitt R L, Ross J L, Zinn A R. Physical mapping of nine Xq translocation breakpoints and identification of XPNPEP2 as a premature ovarian failure candidate gene.  Cytogenet Cell Genet. 2000;  89 44-50
• 53 Duan Q L, Nikpoor B, Dube M P et al.. A variant in XPNPEP2 is associated with angioedema induced by angiotensin I-converting enzyme inhibitors.  Am J Hum Genet. 2005;  77 617-626
• 54 Rizzolio F, Bione S, Villa A et al.. Spatial and temporal expression of POF1B, a gene expressed in epithelia.  Gene Expr Patterns. 2007;  7 529-534
• 55 Lacombe A, Lee H, Zahed L et al.. Disruption of POF1B binding to nonmuscle actin filaments is associated with premature ovarian failure.  Am J Hum Genet. 2006;  79 113-119
• 56 Bione S, Rizzolio F, Sala C et al.. Mutation analysis of two candidate genes for premature ovarian failure, DACH2 and POF1B.  Hum Reprod. 2004;  19 2759-2766
• 57 van Bokhoven H, Schwartz M, Andreasson S et al.. Mutation spectrum in the CHM gene of Danish and Swedish choroideremia patients.  Hum Mol Genet. 1994;  3 1047-1051
• 58 Kleinjan D A, van Heyningen V. Long-range control of gene expression: emerging mechanisms and disruption in disease.  Am J Hum Genet. 2005;  76 8-32
• 59 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;  121 441-450
• 60 Fassnacht W, Mempel A, Strowitzki T, Vogt P H. Premature ovarian failure (POF) syndrome: towards the molecular clinical analysis of its genetic complexity.  Curr Med Chem. 2006;  13 1397-1410
• 61 Kingsley D M. The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms.  Genes Dev. 1994;  8 133-146
• 62 Hogan B L. Bmps: multifunctional regulators of mammalian embryonic development.  Harvey Lect. 1996;  92 83-98
• 63 Drummond A E. TGFbeta signalling in the development of ovarian function.  Cell Tissue Res. 2005;  322 107-115
• 64 Su Y Q, Wu X, O'Brien M J et al.. Synergistic roles of BMP15 and GDF9 in the development and function of the oocyte-cumulus cell complex in mice: genetic evidence for an oocyte-granulosa cell regulatory loop.  Dev Biol. 2004;  276 64-73
• 65 McNatty K P, Juengel J L, Reader K L et al.. Bone morphogenetic protein 15 and growth differentiation factor 9 co-operate to regulate granulosa cell function in ruminants.  Reproduction. 2005;  129 481-487
• 66 Galloway S M, McNatty K P, Cambridge L M 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;  25 279-283
• 67 McNatty K P, Smith P, Moore L G et al.. Oocyte-expressed genes affecting ovulation rate.  Mol Cell Endocrinol. 2005;  234 57-66
• 68 Layman L C. Editorial: BMP15-the first true ovarian determinant gene on the X-chromosome?.  J Clin Endocrinol Metab. 2006;  91 1673-1676
• 69 Layman L C. Mutations in the follicle-stimulating hormone-beta (FSH beta) and FSH receptor genes in mice and humans.  Semin Reprod Med. 2000;  18 5-10
• 70 Verkerk A J, Pieretti M, Sutcliffe J S et al.. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome.  Cell. 1991;  65 905-914
• 71 Oberle I, Rousseau F, Heitz D et al.. Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome.  Science. 1991;  252 1097-1102
• 72 Fu Y H, Kuhl D P, Pizzuti A et al.. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox.  Cell. 1991;  67 1047-1058
• 73 Nolin S L, Brown W T, Glicksman A et al.. Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles.  Am J Hum Genet. 2003;  72 454-464
• 74 Tassone F, Hagerman R J, Taylor A K et al.. Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in the fragile-X syndrome.  Am J Hum Genet. 2000;  66 6-15
• 75 Kenneson A, Zhang F, Hagedorn C H, Warren S T. Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers.  Hum Mol Genet. 2001;  10 1449-1454
• 76 Tassone F, Hagerman P J. Expression of the FMR1 gene.  Cytogenet Genome Res. 2003;  100 124-128
• 77 Feng Y, Zhang F, Lokey L K et al.. Translational suppression by trinucleotide repeat expansion at FMR1.  Science. 1995;  268 731-734
• 78 Primerano B, Tassone F, Hagerman R J et al.. Reduced FMR1 mRNA translation efficiency in fragile X patients with premutations.  RNA. 2002;  8 1482-1488
• 79 Beilina A, Tassone F, Schwartz P H, Sahota P, Hagerman P J. Redistribution of transcription start sites within the FMR1 promoter region with expansion of the downstream CGG-repeat element.  Hum Mol Genet. 2004;  13 543-549
• 80 Hagerman P J, Hagerman R J. The fragile-X premutation: a maturing perspective.  Am J Hum Genet. 2004;  74 805-816
• 81 Schwartz C E, Dean J, Howard-Peebles P N et al.. Obstetrical and gynecological complications in fragile X carriers: a multicenter study.  Am J Med Genet. 1994;  51 400-402
• 82 Allingham-Hawkins D J, Babul-Hirji R, Chitayat D et al.. Fragile X premutation is a significant risk factor for premature ovarian failure: the International Collaborative POF in Fragile X study-preliminary data.  Am J Med Genet. 1999;  83 322-325
• 83 Conway G S, Payne N N, Webb J, Murray A, Jacobs P A. Fragile X premutation screening in women with premature ovarian failure.  Hum Reprod. 1998;  13 1184-1187
• 84 Bretherick K L, Fluker M R, Robinson W P. FMR1 repeat sizes in the gray zone and high end of the normal range are associated with premature ovarian failure.  Hum Genet. 2005;  117 376-382
• 85 Bodega B, Bione S, Dalpra L et al.. Influence of intermediate and uninterrupted FMR1 CGG expansions in premature ovarian failure manifestation.  Hum Reprod. 2005;  , In press
• 86 Uzielli M L, Guarducci S, Lapi E et al.. Premature ovarian failure (POF) and fragile X premutation females: from POF to fragile X carrier identification, from fragile X carrier diagnosis to POF association data.  Am J Med Genet. 1999;  84 300-303
• 87 Murray A, Ennis S, MacSwiney F, Webb J, Morton N E. Reproductive and menstrual history of females with fragile X expansions.  Eur J Hum Genet. 2000;  8 247-252
• 88 Murray A. Premature ovarian failure and the FMR1 gene.  Semin Reprod Med. 2000;  18 59-66
• 89 Murray A, Webb J, MacSwiney F et al.. Serum concentrations of follicle stimulating hormone may predict premature ovarian failure in FRAXA premutation women.  Hum Reprod. 1999;  14 1217-1218
• 90 Hundscheid R D, Braat D D, Kiemeney L A, Smits A P, Thomas C M. Increased serum FSH in female fragile X premutation carriers with either regular menstrual cycles or on oral contraceptives.  Hum Reprod. 2001;  16 457-462
• 91 Hundscheid R D, Sistermans E A, Thomas C M et al.. Imprinting effect in premature ovarian failure confined to paternally inherited fragile X premutations.  Am J Hum Genet. 2000;  66 413-418
• 92 Sullivan A K, Marcus M, Epstein M P et al.. Association of FMR1 repeat size with ovarian dysfunction.  Hum Reprod. 2005;  20 402-412
• 93 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;  14 253-255
• 94 Ebralidze A, Wang Y, Petkova V, Ebralidse K, Junghans R P. RNA leaching of transcription factors disrupts transcription in myotonic dystrophy.  Science. 2004;  303 383-387
• 95 Vegetti W, Grazia Tibiletti M, Testa G et al.. Inheritance in idiopathic premature ovarian failure: analysis of 71 cases.  Hum Reprod. 1998;  13 1796-1800
• 96 Matzuk M M, Lamb D J. Genetic dissection of mammalian fertility pathways.  Nat Cell Biol. 2002;  4(suppl) s41-s49