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Semin Reprod Med 2001; 19(2): 175-182
DOI: 10.1055/s-2001-15397
Copyright © 2001 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Skewed X Inactivation and Recurrent Spontaneous Abortion

W. P. Robinson1 , C. Beever1 , C. J. Brown1 , M. D. Stephenson2 3
  • 1Department of Medical Genetics, University of British Columbia
  • 2Department of Obstetrics and Gynecology, University of British Columbia
  • 3Children's & Women's Health Centre of British Columbia, Vancouver, BC, Canada
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Publication History

Publication Date:
31 December 2001 (online)

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ABSTRACT

Recent studies show that women experiencing recurrent spontaneous abortion exhibit nonrandom X-chromosome inactivation (XCI) more often than in controls. This suggests that genetic factors may be important in explaining the losses in this subset of women. Nonetheless there are a number of possible explanations for this finding and the underlying causes may be heterogeneous. One hypothesis commonly cited is that a mutation on the X chromosome results in both preferential inactivation of the mutated X as well as lethality of male embryos inheriting this mutated X. However, this hypothesis does not explain the increase in chromosome abnormalities observed in the karyotyped losses from women with recurrent pregnancy loss and skewed XCI. This finding leads us to suggest that the mechanism involved may be associated with a reduction in number of ovarian follicles, either due to X mutations affecting oocyte atresia or a restriction in precursor pool size during development.

KEYWORD

X chromosome inactivation - follicular atresia - aneuploidy - pregnancy loss - miscarriage

REFERENCES

  • 1 Stirrat G M. Recurrent miscarriage II: clinical associations, causes, and management.  Lancet . 1990;  336 728-733
    CrossrefPubMedGoogle Scholar
  • 2 Roman E. Fetal loss rates and their relation to pregnancy order.  J Epidemiol Community Health . 1984;  38 29-35
    CrossrefPubMedGoogle Scholar
  • 3 Sangha K K, Stephenson M D, Brown C J, Robinson W P. Extremely skewed X-chromosome inactivation is increased in women with recurrent spontaneous abortion.  Am J Hum Genet . 1999;  65 913-917
    CrossrefPubMedGoogle Scholar
  • 4 Lanasa M C, Hogge W A, Kubik C, Blancato J, Hoffman E P. Highly skewed X-chromosome inactivation is associated with idiopathic recurrent spontaneous abortion.  Am J Hum Genet . 1999;  65 252-254
    CrossrefPubMedGoogle Scholar
  • 5 Hassold T, Abruzzo M, Adkins K. Human aneuploidy: incidence, origin and etiology.  Environ Mol Mutagen . 1996;  28 167-175
    CrossrefPubMedGoogle Scholar
  • 6 Hassold T, Jacobs P. Trisomy in man.  Annu Rev Genet . 1984;  18 69-97
    CrossrefPubMedGoogle Scholar
  • 7 Hassold T, Chiu D. Maternal age-specific rates of numerical chromosome abnormalities with special reference to trisomy.  Hum Genet . 1985;  70 11-17
    CrossrefPubMedGoogle Scholar
  • 8 Ogasawara M, Aoki K, Okada S, Suzumori K. Embryonic karyotype of abortuses in relation to the number of previous miscarriages.  Fertil Steril . 2000;  73 300-304
    CrossrefPubMedGoogle Scholar
  • 9 Stephenson M. Frequency of factors associated with habitual abortion.  Fertil Steril . 1996;  66 24-29
    PubMedGoogle Scholar
  • 10 Lyon M F. Gene action in the X-chromosome of the mouse (Mus musculus L).  Nature . 1961;  190 372-373
    CrossrefPubMedGoogle Scholar
  • 11 Gardner R L, Lyon M F. X chromosome inactivation studied by injection of a single cell into the mouse blastocyst.  Nature . 1971;  231 385-386
    PubMedGoogle Scholar
  • 12 Tan S-S, Williams E A, Tam P PL. X-chromosome inactivation occurs at different times in different tissues of the post-implantation mouse embryo.  Nat Genet . 1993;  3 170-174
    CrossrefPubMedGoogle Scholar
  • 13 Sharp A, Robinson D, Jacobs P. Age- and tissue-specific variation of X chromosome inactivation ratios in normal women.  Hum Genet . 2000;  107 343-349
    CrossrefPubMedGoogle Scholar
  • 14 Abkowitz J L, Taboada M, Shelton G H, Catlin S N, Gutorp P, Kiklevich J V. An X-chromosome gene regulates hematopoietic stem cell kinetics.  Proc Natl Acad Sci U S A . 1998;  95 3862-3866
    CrossrefPubMedGoogle Scholar
  • 15 Christensen K, Kristiansen M, Hagen-Larsen H. X-linked genetic factors regulate hematopoietic stem-cell kinetics in females.  Blood . 2000;  95 2449-2451
    PubMedGoogle Scholar
  • 16 Gale R E, Fielding A K, Harrison C N, Linch D C. Acquired skewing of X-chromosome inactivation patterns in myeloid cells of the elderly suggests stochastic clonal loss with age.  Br J Haematol . 1997;  98 512-519
    CrossrefPubMedGoogle Scholar
  • 17 Beever C L, Stephenson M D, Papovska V. Clinical associations of women experiencing recurrent spontaneous abortion (RSA) and exhibiting skewed X chromosome inactivation (XCI).  Am J Hum Genet Suppl . 2000;  67 166
    PubMedGoogle Scholar
  • 18 Busque L, Mio R, Mattioli J. Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age.  Blood . 1996;  88 59-65
    PubMedGoogle Scholar
  • 19 Luzzatto L, Usanga E A, Bienzle U, Esan G FJ, Fasuan F A. Imbalance in X-chromosome expression: evidence for a human X-linked gene affecting growth of hemopoietic cells.  Science . 1979;  205 1418-1420
    PubMedGoogle Scholar
  • 20 Schmidt M, Du Sart D. Functional disomies of the X-chromosome influence the cell selection and hence the X-inactivation pattern in females with balanced X-autosome translocations.  Am J Med Genet . 1992;  42 161-169
    PubMedGoogle Scholar
  • 21 Migeon B R, Moser H W, Moser A B, Axelman J, Sillence D, Norum R A. Adrenoleukodystrophy: evidence for X linkage, inactivation, and selection favoring the mutant allele in heterozygous cells.  Proc Natl Acad Sci U S A . 1981;  78 5066-5070
    PubMedGoogle Scholar
  • 22 Pegoraro E, Whitakerr J, Mowery-Rushton P, Surti U, Lanasa M, Hoffman E P. Familial skewed X-inactivation: a molecular trait associated with high spontaneous abortion rate maps to Xq28.  Am J Hum Genet . 1997;  61 160-170
    CrossrefPubMedGoogle Scholar
  • 23 Belmont J W. Genetic control of X inactivation and processes leading to X-inactivation skewing.  Am J Hum Genet . 1996;  58 1101-1108
    PubMedGoogle Scholar
  • 24 Gaal M, Laszlo J. X inactivation pattern in an unbalanced X-autosome translocation with gonadal dysgenesis.  Hum Hered . 1977;  27 396-402
    PubMedGoogle Scholar
  • 25 Portnoi M F, Joye N, Van Den Akker J, Morlie G, Taillemite J L. Karyotypes of 1142 couples with recurrent abortion.  Obstet Gynecol . 1988;  72 31-34
    PubMedGoogle Scholar
  • 26 Parrish J E, Scheuerle A E, Lewis R A, Levy M L, Nelson D L. Selection against mutant alleles in blood leukocytes is a consistent feature in incontinentia pigmenti type 2.  Hum Mol Genet . 1996;  5 1777-1783
    CrossrefPubMedGoogle Scholar
  • 27 Migeon B R, Axelman J, de Beur J S, Valle D, Mitchell G A, Rosenbaum K N. Selection against lethal alleles in females heterozygous for incontinentia pigmenti.  Am J Hum Genet . 1989;  44 100-106
    PubMedGoogle Scholar
  • 28 Evsikov S, Verlinsky Y. Mosaicism in the inner cell mass of human blastocysts.  Hum Reprod . 1998;  11 3151-3155
    PubMedGoogle Scholar
  • 29 Harrison R H, Kuo H C, Scriven P N, Handyside A H, Ogilvie C M. Lack of cell cycle checkpoints in human cleavage stage embryos revealed by a clonal pattern of chromosomal mosaicism analyzed by sequential multicolour FISH.  Zygote . 2000;  8 217-224
    CrossrefPubMedGoogle Scholar
  • 30 Ruangvutilert P, Delhanty J DA, Serhal P, Simopoulou M, Rodeck C H, Harper J C. FISH analysis on day 5 post-insemination of human arrested and blastocyst stage embryos.  Prenat Diagn . 2000;  20 552-560
    CrossrefPubMedGoogle Scholar
  • 31 Mark H F, Bier J A. Disappearing trisomy 8 mosaicism.  Ann Clin Lab Sci . 1997;  27 293-298
    PubMedGoogle Scholar
  • 32 Serra A, Arpaia E, Bova R. Kinetics of 21-trisomic lymphocytes.  Hum Genet . 1978;  41 157-67
    PubMedGoogle Scholar
  • 33 Wilson M G, Towner J W, Forsman I. Decreasing mosaicism in Down's syndrome.  Clin Genet . 1980;  17 335-340
    PubMedGoogle Scholar
  • 34 Howard P J, Cramp C E, Fryer A E. Trisomy 1 mosaicism only detected on a direct chromosome preparation in a neonate.  Clin Genet . 1995;  48 313-316
    PubMedGoogle Scholar
  • 35 Kalousek D K.. The effect of confined placental mosaicism on development of the human aneuploid conceptus. In: Blastogenesis: Normal and Abnormal Vol 29(1). New York: Wiley-Liss 1993: 39-51
    Google Scholar
  • 36 Lau A W, Brown C J, Langlois S, Kalousek D K, Robinson W P. Skewed X-chromosome inactivation is common in fetuses or newborns associated with confined placental mosaicism.  Am J Hum Genet . 1997;  61 1353-1361
    CrossrefPubMedGoogle Scholar
  • 37 Peñaherrera M S, Barrett I J, Brown C J. An association between skewed X-chromosome inactivation and abnormal outcome in mosaic trisomy 16 confined predominantly to the placenta.  Clin Genet . 2000;  58 436-446
    CrossrefPubMedGoogle Scholar
  • 38 Buehr M. The primordial germ cells of mammals: some current perspectives.  Exp Cell Res . 1997;  232 194-207
    CrossrefPubMedGoogle Scholar
  • 39 Stavropoulos D J, Bick D, Kalousek D K. Molecular cytogenetic detection of confined gonadal mosaicism in a conceptus with trisomy 16 placental mosaicism.  Am J Hum Genet . 1998;  63 1912-1914
    CrossrefPubMedGoogle Scholar
  • 40 Satge D, Geneix A, Goburdhun J. A history of miscarriages and mild prognathism as possible mode of presentation of mosaic trisomy 18 in women.  Clin Genet . 1996;  50 470-473
    PubMedGoogle Scholar
  • 41 Kohn G, Shohat M. Trisomy 18 mosaicism in an adult with normal intelligence.  Am J Med Genet . 1987;  26 929-931
    CrossrefPubMedGoogle Scholar
  • 42 Nielsen K G, Poulsen H, Mikkelsen M, Steuber E. Multiple recurrence of trisomy 21 Down syndrome.  Hum Genet . 1988;  78 103-105
    PubMedGoogle Scholar
  • 43 Sachs E S, Jahoda M G, Los F J, Pijpers L, Wladimiroff J W. Trisomy 21 mosaicism in gonads with unexpectedly high recurrence risks.  Am J Med Genet Suppl . 1990;  7 186-188
    PubMedGoogle Scholar
  • 44 Gersdorf E, Utermann B, Uttermann G. Trisomy 18 mosaicism in an adult woman with normal intelligence and history of miscarriage.  Hum Genet . 1990;  84 298-299
    PubMedGoogle Scholar
  • 45 Pangalos C G, Talbot C C, Lewis J G. DNA polymorphism analysis in families with recurrence of free trisomy 21.  Am J Hum Genet . 1992;  51 1015-1027
    PubMedGoogle Scholar
  • 46 Tseng L H, Chuang S M, Lee T Y, Ko T M. Recurrent Down's syndrome due to maternal ovarian trisomy 21 mosaicism.  Arch Gynecol Obstet . 1994;  255 213-216
    CrossrefPubMedGoogle Scholar
  • 47 Schupf N, Zigman W, Kapell D, Lee J H, Kline J, Levin B. Early menopause in women with Down's syndrome.  J Intellect Disabil Res . 1997;  41 264-267
    CrossrefPubMedGoogle Scholar
  • 48 Freeman S B, Yang Q, Allran K, Taft L F, Sherman S L. Women with a reduced ovarian complement may have an increased risk for a child with Down syndrome.  Am J Hum Genet . 2000;  66 1680-1683
    CrossrefPubMedGoogle Scholar
  • 49 Kline J, Kinney A, Levin B, Warburton D. Trisomic pregnancy and earlier age at menopause.  Am J Hum Genet . 2000;  67 395-404
    CrossrefPubMedGoogle Scholar
  • 50 Canipari R. Oocyte-granulosa cell interactions.  Hum Reprod Update . 2000;  6 279-289
    CrossrefPubMedGoogle Scholar
  • 51 Delhanty J DA, Harper J C, Ao A, Hanyside A H, Winston R ML. Multicolour FISH detects frequent chromosomal mosaicism and chaotic division in normal preimplantation embryos from fertile patients.  Hum Genet . 1997;  99 755-760
    CrossrefPubMedGoogle Scholar
  • 52 Wells D, Delhanty J D. Comprehensive chromosomal analysis of human preimplantation embryos using whole genome amplification and single cell comparative genomic hybridization.  Mol Hum Reprod . 2000;  6 1055-1061
    CrossrefPubMedGoogle Scholar
  • 53 Plenge R M, Hendrich B D, Schwartz C. A promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation.  Nat Genet . 1997;  17 353-356
    PubMedGoogle Scholar
  • 54 Kristiansen M, Knudsen G P, Hagen C B, ;oFrstavik K H. X inactivation pattern in females with recurrent spontaneous abortions. International symposium on X-chromosome inactivation in mammals. Novosibirsk, Russia, September 6-12, 1999
    Google Scholar
  • 55 Nelson L M, Branch W, Ward K. Highly-skewed X- inactivation patterns are associated with many patients presenting with idiopathic recurrent pregnancy loss.  Am J Hum Genet . 2000;  67 43
    PubMedGoogle Scholar
  • 56 Brown C J, Robinson W P. The causes and consequences of random and nonrandom X chromosome inactivation in humans.  Clin Genet . 2000;  58 353-363
    CrossrefPubMedGoogle Scholar
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