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Semin Reprod Med 2000; 18(1): 097-104
DOI: 10.1055/s-2000-13480
Copyright © 2000 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

X Chromosome Defects as an Etiology of Recurrent Spontaneous Abortion

Mark C. Lanasa1,3 , W. Allen Hogge2,3
  • 1Biochemistry and Molecular Genetics, University of Pittsburgh School of Medicine
  • 2Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh School of Medicine
  • 3Magee-Women's Research Institute, Magee-Women's Hospital, Pittsburgh, Pennsylvania
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Publication History

Publication Date:
31 December 2000 (online)

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ABSTRACT

Recurrent spontaneous abortion is a significant problem in women's health, yet it remains a poorly understood phenomenon. Many cases of recurrent spontaneous abortion defy diagnosis, and we predict that a subset of these unexplained cases are caused by previously unknown, recessively inherited genetic causes. Here, we provide background on known genetic factors that contribute to spontaneous abortion and describe a novel X chromosome-based genetic mechanism that may be an important cause of recurrent spontaneous abortion. Recessively inherited defects on the human X chromosome would cause no symptoms in carrier females but would be lethal in utero to male conceptions that receive the defective X. Through investigation of the basic biology of the X chromosome, we propose that the female carriers of such traits can be identified through the molecular finding of skewed X chromosome inactivation. Furthermore, we have observed an association between skewed X chromosome inactivation and recurrent pregnancy loss, supporting the hypothesis that X chromosome defects may be an important, previously unknown cause of recurrent pregnancy loss.

KEYWORD

spontaneous abortion - X-linked recessive lethal inheritance - X chromosome inactivation

REFERENCES

  • 1 Stephenson M D. Frequency of factors associated with habitual abortion in 197 couples.  Fertil Steril . 1996;  66 24-29
    PubMedGoogle Scholar
  • 2 Stray-Petersen B, Stray-Petersen S. Etiologic factors and subsequent reproductive performance in 195 couples with a prior history of habitual abortion.  Am J Obstet Gynecol . 1984;  148 140-146
    CrossrefPubMedGoogle Scholar
  • 3 Harger J H, Archer D F, Marchese S G, Muracca-Clemens M, Garver K L. Etiology of recurrent pregnancy losses and outcome of subsequent pregnancies.  Am J Obstet Gynecol . 1983;  62 574-581
    PubMedGoogle Scholar
  • 4 Hatasaka H H. Recurrent miscarriage: epidemiologic factors, definitions, and incidence.  Clin Obstet Gynecol . 1994;  37 625-634
    CrossrefPubMedGoogle Scholar
  • 5 Campana M, Serra A, Neri G. Role of chromosome aberrations in recurrent abortion: a study of 269 balanced translocations.  Am J Med Genet . 1986;  24 341-356
    CrossrefPubMedGoogle Scholar
  • 6 Conner J M, Ferguson-Smith M A. Essential medical genetics.  Oxford: Blackwell; 1987
    Google Scholar
  • 7 McDonough P G. The role of molecular mutation in recurrent euploidic abortion.  Semin Reprod Endocrinol . 1988;  6 155-164
    PubMedGoogle Scholar
  • 8 Gilchrist D M, Livingston J E, Hurlburt J A, Wilson R. Recurrent spontaneous pregnancy loss: investigation and reproductive follow-up.  J Repro Med . 1991;  36 184-188
    PubMedGoogle Scholar
  • 9 Hall J G. The lethal multiple pterygium syndromes.  Am J Med Genet . 1984;  17 803-807
    CrossrefPubMedGoogle Scholar
  • 10 Foka Z J, Lambropoulos A F, Saravelos H. Factor V Leiden and prothrombin G202 10A mutations, but not methylenetenetrahydofolate reductase C677T, are associated with recurrent miscarriages.  Human Reprod . 2000;  15 458-462
    CrossrefPubMedGoogle Scholar
  • 11 Ridker P M, Miletich J P, Buring J E. Factor V Leiden mutation as a risk factor for recurrent pregnancy loss.  Ann Intern Med . 1998;  128 1000-1003
    PubMedGoogle Scholar
  • 12 Clark D A. Hard science versus phenomenology in reproductive immunology.  Crit Rev Immunol . 1999;  19 509-539
    PubMedGoogle Scholar
  • 13 Christiansen O B. The possible role of classical human leukocyte antigens in recurrent miscarriage.  Am J Repro Immunol . 1999;  42 110-115
    PubMedGoogle Scholar
  • 14 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
  • 15 Lyon M F. X-chromosome inactivation as a system of gene dosage compensation to regulate gene expression.  Prog Nucleic Acid Res Mol Biol . 1989;  36 119-130
    PubMedGoogle Scholar
  • 16 Lyon M F. Gene action in the X chromosome of the mouse (Mus musculus L.) Nature .  1961;  190 372-373
    CrossrefPubMedGoogle Scholar
  • 17 Fialkow P J. Primordial cell pool size and lineage relationships of five human cell types.  Ann Hum Genet . 1973;  37 39-48
    PubMedGoogle Scholar
  • 18 Allen R C, Nachtman R G, Rosenblatt H M, Belmont J W. Application of carrier testing to genetic counseling for X-linked agammaglobulinemia.  Am J Hum Genet . 1994;  54 25-35
    PubMedGoogle Scholar
  • 19 Azofeifa J, Voit T, Hubner C, Cremer M. X-chromosome methylation in manifesting and healthy carriers of dystrophinopathies: concordance of activation ratios among first degree female relatives and skewed inactivation as cause of the affected phenotypes.  Hum Genet . 1995;  96 167-176
    PubMedGoogle Scholar
  • 20 Pegoraro E, Schimke R N, Arahata K. Detection of new paternal dystrophin gene mutations in isolated cases of dystrophinopathy in females.  Am J Hum Genet . 1994;  54 989-100
    PubMedGoogle Scholar
  • 21 Naumova A K, Plenge R M, Bird L M. Heritability of X chromosome-inactivation phenotype in a large family.  Am J Hum Genet . 1996;  58 1111-1119
    PubMedGoogle Scholar
  • 22 Orstavik K H, Orstavik R E, Schwartz M. Skewed X chromosome inactivation in a female with haemophilia B and in her non-carrier daughter: a genetic influence on X chromosome inactivation?.  J Med Genet . 1999;  36 865-866
    PubMedGoogle Scholar
  • 23 Parolini O, Ressmann G, Haas O A. X-linked Wiskott-Aldrich syndrome in a girl.  N Engl J Med. 338 291-295
    PubMedGoogle Scholar
  • 24 Nyhan W L, Bakay B, Connor J D, Marks J F, Keele D K. Hemizygous expression of glucose-6-phosphate dehydrogenase in erythrocytes of heterozygotes for the Lesch-Nyhan syndrome.  Proc Natl Acad Sci U S A . 1970;  65 214-218
    PubMedGoogle Scholar
  • 25 Puck J M, Nussbaum R L, Conley M E. Carrier detection in X-linked severe combined immunodeficiency based on patterns of X chromosome inactivation.  J Clin Invest . 1987;  79 1395-1400
    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. Non-random X chromosome inactivation in mammalian cells.  Cytogenet Cell Genet . 1998;  80 142-148
    CrossrefPubMedGoogle Scholar
  • 28 Lanasa M C, Hogge W A, Hoffman E P. The X chromosome and recurrent spontaneous abortion: the significance of transmanifesting carriers.  Am J Hum Genet . 1999;  64 934-938
    CrossrefPubMedGoogle Scholar
  • 29 Pegoraro E, Whitaker 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
  • 30 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
  • 31 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
  • 32 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
  • 33 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
  • 34 Lau A W, Brown C J, Penaherrera M, 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
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