X-Chromosome Inactivation

  • Wendy P. Robinson
  • Allison M. Cotton
  • Maria S. Peñaherrera
  • Samantha B. Peeters
  • Carolyn J. BrownEmail author


The dimorphism of the sex chromosomes has led to some of the most dramatic epigenetic phenomena known in order to achieve dosage compensation between the sexes. Mammalian X-chromosome inactivation (XCI) requires the differential treatment of two essentially identical chromosomes in the same nuclear environment. XCI has thus been the subject of considerable study in mouse as a paradigm for epigenetic choice, although less is known about the timing and initial events of XCI in humans and other species. XCI, as can be visualized by the spots on a calico cat, is also a dramatic example of the stability of epigenetic silencing, since the inactivation state of an X chromosome (X) is faithfully inherited through subsequent somatic cell divisions. Studies to understand the layering of epigenetic modifications that result in such stable silencing have been reviewed elsewhere, and in this review we focus instead on the translation of our growing understanding of the epigenetic phenomena of XCI to human disease.

X-linked disease is epitomized by an excess of affected males, but the characterization as dominant or recessive belies the complexity of the contribution of XCI. Notably, whether or not X-linked disease is apparent in females is considerably impacted by the extent of skewing of XCI in the individual. Furthermore, the unique biology of the sex chromosomes impacts the likelihood of X-linked disease in females due to de novo mutation rates. In addition, XCI does not result in complete dosage equivalence between males and females; however, the extent to which there are sex, and even interindividual differences due to XCI has not yet been well elucidated. Overall, while it is the Y chromosome (Y) that determines sex, the X contributes in a complex fashion to the sex differences in disease frequency and severity.


Duchenne Muscular Dystrophy Dosage Compensation Premature Ovarian Failure Kallmann Syndrome Allelic Expression Imbalance 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Allen RC, Zoghbi HY, Moseley AB, Rosenblatt HM, Belmont JW (1992) Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet 51:1229–1239PubMedGoogle Scholar
  2. Amos-Landgraf JM, Cottle A, Plenge RM, Friez M, Schwartz CE, Longshore J, Willard HF (2006) X chromosome-inactivation patterns of 1,005 phenotypically unaffected females. Am J Hum Genet 79(3):493–499PubMedGoogle Scholar
  3. Anderson C, Brown CJ (1999) Polymorphic X-chromosome inactivation of the human TIMP1 gene. Am J Hum Genet 65:699–708PubMedGoogle Scholar
  4. Anderson CL, Brown CJ (2005) Epigenetic predisposition to expression of TIMP1 from the human inactive X chromosome. BMC Genet 6:48PubMedGoogle Scholar
  5. Asplund A, Guo Z, Hu X, Wassberg C, Ponten F (2001) Mosaic pattern of maternal and paternal keratinocyte clones in normal human epidermis revealed by analysis of X-chromosome inactivation. J Investig Dermatol 117(1):128–131PubMedGoogle Scholar
  6. Au WY, Lam V, Pang A, Lee WM, Chan JL, Song YQ, Ma ES, Kwong YL (2006) Glucose-6-phosphate dehydrogenase deficiency in female octogenarians, nanogenarians, and centenarians. J Gerontol A Biol Sci Med Sci 61(10):1086–1089PubMedGoogle Scholar
  7. Beever C, Lai BP, Baldry SE, Penaherrera MS, Jiang R, Robinson WP, Brown CJ (2003a) Methylation of ZNF261 as an assay for determining X chromosome inactivation patterns. Am J Med Genet A 120A(3):439–441PubMedGoogle Scholar
  8. Beever CL, Stephenson MD, Penaherrera MS, Jiang RH, Kalousek DK, Hayden M, Field L, Brown CJ, Robinson WP (2003b) Skewed X-chromosome inactivation is associated with trisomy in women ascertained on the basis of recurrent spontaneous abortion or chromosomally abnormal pregnancies. Am J Hum Genet 72(2):399–407PubMedGoogle Scholar
  9. Berletch JB, Yang F, Disteche CM (2010) Escape from X inactivation in mice and humans. Genome Biol 11(6):213PubMedGoogle Scholar
  10. Berletch JB, Yang F, Xu J, Carrel L, Disteche CM (2011) Genes that escape from X inactivation. Hum Genet 130(2):237–245PubMedGoogle Scholar
  11. Bertelsen B, Tumer Z, Ravn K (2011) Three new loci for determining X chromosome inactivation patterns. J Mol Diagn 13(5):537–540PubMedGoogle Scholar
  12. Bianchi I, Lleo A, Gershwin ME, Invernizzi P (2012) The X chromosome and immune associated genes. J Autoimmun 38(2–3):J187–J192PubMedGoogle Scholar
  13. Bittel DC, Theodoro MF, Kibiryeva N, Fischer W, Talebizadeh Z, Butler MG (2008) Comparison of X-chromosome inactivation patterns in multiple tissues from human females. J Med Genet 45(5):309–313PubMedGoogle Scholar
  14. Blewitt ME, Vickaryous NK, Hemley SJ, Ashe A, Bruxner TJ, Preis JI, Arkell R, Whitelaw E (2005) An N-ethyl-N-nitrosourea screen for genes involved in variegation in the mouse. Proc Natl Acad Sci U S A 102(21):7629–7634PubMedGoogle Scholar
  15. Bolduc V, Chagnon P, Provost S, Dube MP, Belisle C, Gingras M, Mollica L, Busque L (2008) No evidence that skewing of X chromosome inactivation patterns is transmitted to offspring in humans. J Clin Investig 118(1):333–341PubMedGoogle Scholar
  16. Boyd Y, Buckle VJ (1986) Cytogenetic heterogeneity of translocations associated with Duchenne muscular dystrophy. Clin Genet 29(2):108–115PubMedGoogle Scholar
  17. Bretherick KL, Metzger DL, Chanoine JP, Panagiotopoulos C, Watson SK, Lam WL, Fluker MR, Brown CJ, Robinson WP (2007) Skewed X-chromosome inactivation is associated with primary but not secondary ovarian failure. Am J Med Genet A 143A(9):945–951PubMedGoogle Scholar
  18. Brown CJ, Willard HF (1994) The human X inactivation center is not required for maintenance of X inactivation. Nature 368:154–156PubMedGoogle Scholar
  19. Busque L, Mio R, Mattioli J, Brais E, Blais N, Lalonde Y, Maragh M, Gilliland DG (1996) Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age. Blood 88:59–65PubMedGoogle Scholar
  20. Busque L, Paquette Y, Provost S, Roy DC, Levine RL, Mollica L, Gilliland DG (2009) Skewing of X-inactivation ratios in blood cells of aging women is confirmed by independent methodologies. Blood 113(15):3472–3474PubMedGoogle Scholar
  21. Busque L, Zhu J, DeHart D, Griffith B, Willman C, Carroll R, Black PM, Gilliland DG (1994) An expression based clonality assay at the human androgen receptor locus (HUMARA) on the X chromosome. Nucleic Acids Res 22:697–698PubMedGoogle Scholar
  22. Butler MG, Theodoro MF, Bittel DC, Kuipers PJ, Driscoll DJ, Talebizadeh Z (2007) X-chromosome inactivation patterns in females with Prader-Willi syndrome. Am J Med Genet A 143(5):469–475PubMedGoogle Scholar
  23. Carrel L, Hunt PA, Willard HF (1996) Tissue and lineage-specific variation in inactive X chromosome expression of the murine Smcx gene. Hum Mol Genet 5:1361–1366PubMedGoogle Scholar
  24. Carrel L, Willard HF (1993) The X-linked choroideremia gene escapes X chromosome inactivation. Am J Hum Genet 53(3):42AGoogle Scholar
  25. Carrel L, Willard HF (2005) X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434(7031):400–404PubMedGoogle Scholar
  26. Cattanach BM, Pollard CE, Perez JN (1969) Controlling elements in the mouse X-chromosome 1. Interaction with the X-linked genes. Genet Res 14:223–235PubMedGoogle Scholar
  27. Cau M, Addis M, Congiu R, Meloni C, Cao A, Santaniello S, Loi M, Emma F, Zuffardi O, Ciccone R, Sole G, Melis MA (2006) A locus for familial skewed X chromosome inactivation maps to chromosome Xq25 in a family with a female manifesting Lowe syndrome. J Hum Genet 51(11):1030–1036PubMedGoogle Scholar
  28. Cazzola M, May A, Bergamaschi G, Cerani P, Rosti V, Bishop DF (2000) Familial-skewed X-chromosome inactivation as a predisposing factor for late-onset X-linked sideroblastic anemia in carrier females. Blood 96(13):4363–4365PubMedGoogle Scholar
  29. Chaturvedi V, Chu MS, Carrol BM, Brenner BJ, Nickoloff BJ (2002) Estimation of size of clonal unit for keratinocytes in normal human skin. Arch Pathol Lab Med 126(4):420–424PubMedGoogle Scholar
  30. Chelly J, Marlhens F, Le Marec B, Jeanpierre M, Lambert M, Hamard G, Dutrillaux B, Kaplan JC (1986) De novo DNA microdeletion in a girl with Turner syndrome and Duchenne muscular dystrophy. Hum Genet 74(2):193–196PubMedGoogle Scholar
  31. Chen GL, Prchal JT (2007) X-linked clonality testing: interpretation and limitations. Blood 110(5):1411–1419PubMedGoogle Scholar
  32. Chitnis S, Derom C, Vlietinck R, Derom R, Monteiro J, Gregersen PK (1999) X chromosome-inactivation patterns confirm the late timing of monamniotic-MZ twinning. Am J Hum Genet 65:570–571PubMedGoogle Scholar
  33. Christensen K, Kristiansen M, Hagen-Larsen H, Skytthe A, Bathum L, Jeune B, Andersen-Ranberg K, Vaupel JW, Orstavik KH (2000) X-linked genetic factors regulate hematopoietic stem-cell kinetics in females. Blood 95:2449–2451PubMedGoogle Scholar
  34. Chung IM, Schwartz SM, Murry CE (1998) Clonal architecture of normal and atherosclerotic aorta: implications for atherogenesis and vascular development. Am J Pathol 152(4):913–923PubMedGoogle Scholar
  35. Clements SE, Mellerio JE, Holden ST, McCauley J, McGrath JA (2009) PORCN gene mutations and the protean nature of focal dermal hypoplasia. Br J Dermatol 160(5):1103–1109PubMedGoogle Scholar
  36. Cotton AM, Lam L, Affleck JG, Wilson IM, Penaherrera MS, McFadden DE, Kobor MS, Lam WL, Robinson WP, Brown CJ (2011) Chromosome-wide DNA methylation analysis predicts human tissue-specific X inactivation. Hum Genet 130(2):187–201PubMedGoogle Scholar
  37. D'Esposito M, Ciccodicola A, Gianfrancesco F, Esposito T, Flagiello L, Mazzarella R, Schlessinger D, D'Urso M (1996) A synaptobrevin-like gene in the Xq28 pseudoautosomal region undergoes X inactivation. Nat Genet 13(2):227–229PubMedGoogle Scholar
  38. Dayer AG, Bottani A, Bouchardy I, Fluss J, Antonarakis SE, Haenggeli CA, Morris MA (2007) MECP2 mutant allele in a boy with Rett syndrome and his unaffected heterozygous mother. Brain Dev 29(1):47–50PubMedGoogle Scholar
  39. De Bonis ML, Cerase A, Matarazzo MR, Ferraro M, Strazzullo M, Hansen RS, Chiurazzi P, Neri G, D’Esposito M (2006) Maintenance of X- and Y-inactivation of the pseudoautosomal (PAR2) gene SPRY3 is independent from DNA methylation and associated to multiple layers of epigenetic modifications. Hum Mol Genet 15(7):1123–1132PubMedGoogle Scholar
  40. Deng X, Hiatt JB, Nguyen DK, Ercan S, Sturgill D, Hillier LW, Schlesinger F, Davis CA, Reinke VJ, Gingeras TR, Shendure J, Waterston RH, Oliver B, Lieb JD, Disteche CM (2011) Evidence for compensatory upregulation of expressed X-linked genes in mammals, Caenorhabditis elegans and Drosophila melanogaster. Nat Genet 43(12):1179–1185PubMedGoogle Scholar
  41. Di Nunzio S, Cecconi M, Passerini L, McMurchy AN, Baron U, Turbachova I, Vignola S, Valencic E, Tommasini A, Junker A, Cazzola G, Olek S, Levings MK, Perroni L, Roncarolo MG, Bacchetta R (2009) Wild-type FOXP3 is selectively active in CD4 + CD25(hi) regulatory T cells of healthy female carriers of different FOXP3 mutations. Blood 114(19):4138–4141PubMedGoogle Scholar
  42. Diallo R, Schaefer KL, Poremba C, Shivazi N, Willmann V, Buerger H, Dockhorn-Dworniczak B, Boecker W (2001) Monoclonality in normal epithelium and in hyperplastic and neoplastic lesions of the breast. J Pathol 193(1):27–32PubMedGoogle Scholar
  43. Dobrovolny R, Dvorakova L, Ledvinova J, Magage S, Bultas J, Lubanda JC, Elleder M, Karetova D, Pavlikova M, Hrebicek M (2005) Relationship between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the alpha-galactosidase A gene in the Czech and Slovak population. J Mol Med 83(8):647–654PubMedGoogle Scholar
  44. Dobyns WB, Filauro A, Tomson BN, Chan AS, Ho AW, Ting NT, Oosterwijk JC, Ober C (2004) Inheritance of most X-linked traits is not dominant or recessive, just X-linked. Am J Med Genet A 129A(2):136–143PubMedGoogle Scholar
  45. Durmaz E, Zou M, Al-Rijjal RA, Baitei EY, Hammami S, Bircan I, Akcurin S, Meyer B, Shi Y (2013) Novel and de novo PHEX mutations in patients with hypophosphatemic rickets. Bone 52(1):286–289PubMedGoogle Scholar
  46. Francke U, Felsenstein J, Gartler SM, Migeon BR, Dancis J, Seegmiller JE, Bakay F, Nyhan WL (1976) The occurrence of new mutants in the X-linked recessive Lesch-Nyhan disease. Am J Hum Genet 28:123–137PubMedGoogle Scholar
  47. Gale RE, Linch DC (1998) Clonality studies in acute myeloid leukemia. Leukemia 12(2):117–120PubMedGoogle Scholar
  48. Gale RE, Wheadon H, Boulos P, Linch DC (1994) Tissue specificity of X-chromosome inactivation patterns. Blood 83:2899–2905PubMedGoogle Scholar
  49. Gentilini D, Castaldi D, Mari D, Monti D, Franceschi C, Di Blasio AM, Vitale G (2012) Age-dependent skewing of X chromosome inactivation appears delayed in centenarians' offspring. Is there a role for allelic imbalance in healthy aging and longevity? Aging Cell 11(2):277–283PubMedGoogle Scholar
  50. Gibbons RJ, Suthers GK, Wilkie AO, Buckle VJ, Higgs DR (1992) X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome: localization to Xq12-q21.31 by X inactivation and linkage analysis. Am J Hum Genet 51:1136–1149PubMedGoogle Scholar
  51. Green PM, Saad S, Lewis CM, Giannelli F (1999) Mutation rates in humans. I. Overall and sex-specific rates obtained from a population study of hemophilia B. Am J Hum Genet 65(6):1572–1579PubMedGoogle Scholar
  52. Grimm T, Meng G, Liechti-Gallati S, Bettecken T, Muller CR, Muller B (1994) On the origin of deletions and point mutations in Duchenne muscular dystrophy: most deletions arise in oogenesis and most point mutations result from events in spermatogenesis. J Med Genet 31(3):183–186PubMedGoogle Scholar
  53. Hatakeyama C, Anderson CL, Beever CL, Penaherrera MS, Brown CJ, Robinson WP (2004) The dynamics of X-inactivation skewing as women age. Clin Genet 66(4):327–332PubMedGoogle Scholar
  54. Hogge WA, Prosen TL, Lanasa MC, Huber HA, Reeves MF (2007) Recurrent spontaneous abortion and skewed X-inactivation: is there an association? Am J Obstet Gynecol 196(4):384, e381–386Google Scholar
  55. Hopkins IJ, Humphrey I, Keith CG, Susman M, Webb GC, Turner EK (1979) The Aicardi syndrome in a 47, XXY male. Aust Paediatr J 15(4):278–280PubMedGoogle Scholar
  56. Jobanputra V, Levy B, Kinney A, Brown S, Shirazi M, Yu C, Kline J, Warburton D (2012) Copy number changes on the X chromosome in women with and without highly skewed X-chromosome inactivation. Cytogenet Genome Res 136(4):264–269PubMedGoogle Scholar
  57. Jovanovic L, Delahunt B, McIver B, Eberhardt NL, Grebe SK (2003) Thyroid gland clonality revisited: the embryonal patch size of the normal human thyroid gland is very large, suggesting X-chromosome inactivation tumor clonality studies of thyroid tumors have to be interpreted with caution. J Clin Endocrinol Metab 88(7):3284–3291PubMedGoogle Scholar
  58. Juriloff DM, Harris MJ (2012) Hypothesis: The female excess in cranial neural tube defects reflects an epigenetic drag of the inactivating x chromosome on the molecular mechanisms of neural fold elevation. Birth Defects Res A Clin Mol Teratol 94(10):849–855PubMedGoogle Scholar
  59. Knudsen GP, Pedersen J, Klingenberg O, Lygren I, Orstavik KH (2007) Increased skewing of X chromosome inactivation with age in both blood and buccal cells. Cytogenet Genome Res 116(1–2):24–28PubMedGoogle Scholar
  60. Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, Magnusson G, Gudjonsson SA, Sigurdsson A, Jonasdottir A, Jonasdottir A, Wong WS, Sigurdsson G, Walters GB, Steinberg S, Helgason H, Thorleifsson G, Gudbjartsson DF, Helgason A, Magnusson OT, Thorsteinsdottir U, Stefansson K (2012) Rate of de novo mutations and the importance of father’s age to disease risk. Nature 488(7412):471–475PubMedGoogle Scholar
  61. Kristiansen M, Knudsen GP, Bathum L, Naumova AK, Sorensen TI, Brix TH, Svendsen AJ, Christensen K, Kyvik KO, Orstavik KH (2005) Twin study of genetic and aging effects on X chromosome inactivation. Eur J Hum Genet 13(5):599–606PubMedGoogle Scholar
  62. Kubota T, Nonoyama S, Tonoki H, Masuno M, Imaizumi K, Kojima M, Wakui K, Shimadzu M, Fukushima Y (1999) A new assay for the analysis of X-chromosome inactivation based on methylation-specific PCR. Hum Genet 104(1):49–55PubMedGoogle Scholar
  63. Kucera KS, Reddy TE, Pauli F, Gertz J, Logan JE, Myers RM, Willard HF (2011) Allele-specific distribution of RNA polymerase II on female X chromosomes. Hum Mol Genet 20(20):3964–3973PubMedGoogle Scholar
  64. Lahn BT, Page DC (1999) Four evolutionary strata on the human X chromosome. Science 286:964–967PubMedGoogle Scholar
  65. Lanasa MC, Hogge WA, Kubik C, Blancato J, Hoffman EP (1999) Highly skewed X-chromosome inactivation is associated with idiopathic recurrent spontaneous abortion. Am J Hum Genet 65(1):252–254PubMedGoogle Scholar
  66. Lau AW, Brown CJ, Penaherrera M, Langlois S, Kalousek DK, Robinson WP (1997) Skewed X-chromosome inactivation is common in fetuses or newborns associated with confined placental mosaicism. Am J Hum Genet 61:1353–1361PubMedGoogle Scholar
  67. Leppig KA, Disteche CM (2001) Ring X and other structural X chromosome abnormalities: X inactivation and phenotype. Semin Reprod Med 19(2):147–157. doi: 10.1055/s-2001-15395 PubMedGoogle Scholar
  68. Leuer M, Oldenburg J, Lavergne JM, Ludwig M, Fregin A, Eigel A, Ljung R, Goodeve A, Peake I, Olek K (2001) Somatic mosaicism in hemophilia A: a fairly common event. Am J Hum Genet 69(1):75–87PubMedGoogle Scholar
  69. Lingenfelter PA, Adler DA, Poslinski D, Thomas S, Elliot RW, Chapman VM, Disteche CM (1998) Escape from X inactivation of Smcx is preceded by silencing during mouse development. Nat Genet 18:212–213PubMedGoogle Scholar
  70. Livernois AM, Graves JA, Waters PD (2012) The origin and evolution of vertebrate sex chromosomes and dosage compensation. Heredity (Edinb) 108(1):50–58Google Scholar
  71. Lyon MF (1962) Sex chromatin and gene action in the mammalian X-chromosome. Am J Hum Genet 14:135–145PubMedGoogle Scholar
  72. Migeon BR (2006) The role of X inactivation and cellular mosaicism in women's health and sex-specific diseases. JAMA 295(12):1428–1433PubMedGoogle Scholar
  73. Migeon BR, Shapiro LJ, Norum RA, Mohandas T, Axelman J, Dabora RL (1982) Differential expression of steriod sulphatase locus on active and inactive human X chromosome. Nature 299:838–840PubMedGoogle Scholar
  74. Minks J, Robinson WP, Brown CJ (2008) A skewed view of X chromosome inactivation. J Clin Investig 118(1):20–23PubMedGoogle Scholar
  75. Monteiro J, Derom C, Vlietinck R, Kohn N, Lesser M, Gregersen PK (1998) Commitment to X inactivation precedes the twinning event in monochorionic MZ twins. Am J Hum Genet 63:339–346PubMedGoogle Scholar
  76. Mutter GL, Boynton KA, Faquin WC, Ruiz RE, Jovanovic AS (1996) Allelotype mapping of unstable microsatellites establishes direct lineage continuity between endometrial precancers and cancer. Cancer Res 56(19):4483–4486PubMedGoogle Scholar
  77. Naumova AK, Olien L, Bird LM, Smith M, Verner AE, Leppert M, Morgan K, Sapienza C (1998) Genetic mapping of X-linked loci involved in skewing of X chromosome inactivation in the human. Eur J Hum Genet 6:552–562PubMedGoogle Scholar
  78. Nguyen DK, Disteche CM (2006) Dosage compensation of the active X chromosome in mammals. Nat Genet 38(1):47–53PubMedGoogle Scholar
  79. Novelli M, Cossu A, Oukrif D, Quaglia A, Lakhani S, Poulsom R, Sasieni P, Carta P, Contini M, Pasca A, Palmieri G, Bodmer W, Tanda F, Wright N (2003) X-inactivation patch size in human female tissue confounds the assessment of tumor clonality. Proc Natl Acad Sci U S A 100(6):3311–3314PubMedGoogle Scholar
  80. Orstavik KH (2009) X chromosome inactivation in clinical practice. Hum Genet 126(3):363–373PubMedGoogle Scholar
  81. Ozbalkan Z, Bagislar S, Kiraz S, Akyerli CB, Ozer HT, Yavuz S, Birlik AM, Calguneri M, Ozcelik T (2005) Skewed X chromosome inactivation in blood cells of women with scleroderma. Arthritis Rheum 52(5):1564–1570PubMedGoogle Scholar
  82. Ozcelik T, Uz E, Akyerli CB, Bagislar S, Mustafa CA, Gursoy A, Akarsu N, Toruner G, Kamel N, Gullu S (2006) Evidence from autoimmune thyroiditis of skewed X-chromosome inactivation in female predisposition to autoimmunity. Eur J Hum Genet 14(6):791–797PubMedGoogle Scholar
  83. Pegoraro E, Whitaker J, Mowery-Rushton P, Surti U, Lanasa M, Hoffman E (1998) Familial skewed X inactivation: a molecular trait associated with high spontaneous-abortion rate maps to Xq28. Am J Hum Genet 61:160–170Google Scholar
  84. Penaherrera MS, Jiang R, Avila L, Yuen RK, Brown CJ, Robinson WP (2012) Patterns of placental development evaluated by X chromosome inactivation profiling provide a basis to evaluate the origin of epigenetic variation. Hum Reprod 27(6):1745–1753PubMedGoogle Scholar
  85. Penny GD, Kay GF, Sheardown SA, Rastan S, Brockdorff N (1996) Requirement for Xist in X chromosome inactivation. Nature 379:131–137PubMedGoogle Scholar
  86. Pereira LV, Zata M (1999) Screening of the C43G mutation in the promoter region of the XIST gene in females with highly skewed X-chromosome inactivation. Am J Med Genet 87:86–87PubMedGoogle Scholar
  87. Pessia E, Makino T, Bailly-Bechet M, McLysaght A, Marais GA (2012) Mammalian X chromosome inactivation evolved as a dosage-compensation mechanism for dosage-sensitive genes on the X chromosome. Proc Natl Acad Sci U S A 109(14):5346–5351PubMedGoogle Scholar
  88. Plenge RM, Hendrich BD, Schwartz C, Arena JF, Naumova A, Sapienza C, Winter RM, Willard HF (1997) A promoter mutation in the XIST gene in two unrelated families with skewed X-chromosome inactivation. Nat Genet 17:353–356PubMedGoogle Scholar
  89. Puck JM, Willard HF (1998) X inactivation in females with X-linked disease. New Engl J Med 338:325–328PubMedGoogle Scholar
  90. Pugacheva EM, Tiwari VK, Abdullaev Z, Vostrov AA, Flanagan PT, Quitschke WW, Loukinov DI, Ohlsson R, Lobanenkov VV (2005) Familial cases of point mutations in the XIST promoter reveal a correlation between CTCF binding and pre-emptive choices of X chromosome inactivation. Hum Mol Genet 14(7):953–965PubMedGoogle Scholar
  91. Renault NKE, Renault MP, Copeland E, Howell RE, Greer WL (2011) Familial skewed X-chromosome inactivation linked to a component of the cohesin complex, SA2. J Hum Genet 56(5):390–397PubMedGoogle Scholar
  92. Richards CS, Watkins SC, Hoffman EP, Schneider NR, Milsark IW, Katz KS, Cook JD, Kunkel LM, Cortada JM (1990) Skewed X inactivation in a female MZ twin results in Duchenne muscular dystrophy. Am J Hum Genet 46(4):672–681PubMedGoogle Scholar
  93. Ross MT, Grafham DV, Coffey AJ, Scherer S, McLay K, Muzny D, Platzer M, Howell GR, Burrows C, Bird CP, Frankish A, Lovell FL, Howe KL, Ashurst JL, Fulton RS, Sudbrak R, Wen G, Jones MC, Hurles ME, Andrews TD, Scott CE, Searle S, Ramser J, Whittaker A, Deadman R, Carter NP, Hunt SE, Chen R, Cree A, Gunaratne P, Havlak P, Hodgson A, Metzker ML, Richards S, Scott G, Steffen D, Sodergren E, Wheeler DA, Worley KC, Ainscough R, Ambrose KD, Ansari-Lari MA, Aradhya S, Ashwell RI, Babbage AK, Bagguley CL, Ballabio A, Banerjee R, Barker GE, Barlow KF, Barrett IP, Bates KN, Beare DM, Beasley H, Beasley O, Beck A, Bethel G, Blechschmidt K, Brady N, Bray-Allen S, Bridgeman AM, Brown AJ, Brown MJ, Bonnin D, Bruford EA, Buhay C, Burch P, Burford D, Burgess J, Burrill W, Burton J, Bye JM, Carder C, Carrel L, Chako J, Chapman JC, Chavez D, Chen E, Chen G, Chen Y, Chen Z, Chinault C, Ciccodicola A, Clark SY, Clarke G, Clee CM, Clegg S, Clerc-Blankenburg K, Clifford K, Cobley V, Cole CG, Conquer JS, Corby N, Connor RE, David R, Davies J, Davis C, Davis J, Delgado O, Deshazo D, Dhami P, Ding Y, Dinh H, Dodsworth S, Draper H, Dugan-Rocha S, Dunham A, Dunn M, Durbin KJ, Dutta I, Eades T, Ellwood M, Emery-Cohen A, Errington H, Evans KL, Faulkner L, Francis F, Frankland J, Fraser AE, Galgoczy P, Gilbert J, Gill R, Glockner G, Gregory SG, Gribble S, Griffiths C, Grocock R, Gu Y, Gwilliam R, Hamilton C, Hart EA, Hawes A, Heath PD, Heitmann K, Hennig S, Hernandez J, Hinzmann B, Ho S, Hoffs M, Howden PJ, Huckle EJ, Hume J, Hunt PJ, Hunt AR, Isherwood J, Jacob L, Johnson D, Jones S, de Jong PJ, Joseph SS, Keenan S, Kelly S, Kershaw JK, Khan Z, Kioschis P, Klages S, Knights AJ, Kosiura A, Kovar-Smith C, Laird GK, Langford C, Lawlor S, Leversha M, Lewis L, Liu W, Lloyd C, Lloyd DM, Loulseged H, Loveland JE, Lovell JD, Lozado R, Lu J, Lyne R, Ma J, Maheshwari M, Matthews LH, McDowall J, McLaren S, McMurray A, Meidl P, Meitinger T, Milne S, Miner G, Mistry SL, Morgan M, Morris S, Muller I, Mullikin JC, Nguyen N, Nordsiek G, Nyakatura G, O’Dell CN, Okwuonu G, Palmer S, Pandian R, Parker D, Parrish J, Pasternak S, Patel D, Pearce AV, Pearson DM, Pelan SE, Perez L, Porter KM, Ramsey Y, Reichwald K, Rhodes S, Ridler KA, Schlessinger D, Schueler MG, Sehra HK, Shaw-Smith C, Shen H, Sheridan EM, Shownkeen R, Skuce CD, Smith ML, Sotheran EC, Steingruber HE, Steward CA, Storey R, Swann RM, Swarbreck D, Tabor PE, Taudien S, Taylor T, Teague B, Thomas K, Thorpe A, Timms K, Tracey A, Trevanion S, Tromans AC, d’Urso M, Verduzco D, Villasana D, Waldron L, Wall M, Wang Q, Warren J, Warry GL, Wei X, West A, Whitehead SL, Whiteley MN, Wilkinson JE, Willey DL, Williams G, Williams L, Williamson A, Williamson H, Wilming L, Woodmansey RL, Wray PW, Yen J, Zhang J, Zhou J, Zoghbi H, Zorilla S, Buck D, Reinhardt R, Poustka A, Rosenthal A, Lehrach H, Meindl A, Minx PJ, Hillier LW, Willard HF, Wilson RK, Waterston RH, Rice CM, Vaudin M, Coulson A, Nelson DL, Weinstock G, Sulston JE, Durbin R, Hubbard T, Gibbs RA, Beck S, Rogers J, Bentley DR (2005) The DNA sequence of the human X chromosome. Nature 434(7031):325–337PubMedGoogle Scholar
  94. Ryan SG, Chance PF, Zou CH, Spinner NB, Golden JA, Smietana S (1997) Epilepsy and mental retardation limited to females: an X-linked dominant disorder with male sparing. Nat Genet 17(1):92–95PubMedGoogle Scholar
  95. Salsano E, Tabano S, Sirchia SM, Colapietro P, Castellotti B, Gellera C, Rimoldi M, Pensato V, Mariotti C, Pareyson D, Miozzo M, Uziel G (2012) Preferential expression of mutant ABCD1 allele is common in adrenoleukodystrophy female carriers but unrelated to clinical symptoms. Orphanet J Rare Dis 7:10PubMedGoogle Scholar
  96. Sato K, Uehara S, Hashiyada M, Nabeshima H, Sugawara J, Terada Y, Yaegashi N, Okamura K (2004) Genetic significance of skewed X-chromosome inactivation in premature ovarian failure. Am J Med Genet A 130A(3):240–244PubMedGoogle Scholar
  97. Schluth C, Cossee M, Girard-Lemaire F, Carelle N, Dollfus H, Jeandidier E, Flori E (2007) Phenotype in X chromosome rearrangements: pitfalls of X inactivation study. Pathol Biol 55(1):29–36PubMedGoogle Scholar
  98. Sharp A, Robinson D, Jacobs P (2000) Age- and tissue-specific variation of X chromosome inactivation ratios in normal women. Hum Genet 107(4):343–349PubMedGoogle Scholar
  99. Sharp AJ, Stathaki E, Migliavacca E, Brahmachary M, Montgomery SB, Dupre Y, Antonarakis SE (2011) DNA methylation profiles of human active and inactive X chromosomes. Genome Res 21(10):1592–1600. doi:10.1101/gr.112680.110PubMedGoogle Scholar
  100. Smeets EE, Pelc K, Dan B (2012) Rett syndrome. Mol Syndromol 2(3–5):113–127PubMedGoogle Scholar
  101. Smith-Bouvier DL, Divekar AA, Sasidhar M, Du S, Tiwari-Woodruff SK, King JK, Arnold AP, Singh RR, Voskuhl RR (2008) A role for sex chromosome complement in the female bias in autoimmune disease. J Exp Med 205(5):1099–1108PubMedGoogle Scholar
  102. Stephenson MD, Awartani KA, Robinson WP (2002) Cytogenetic analysis of miscarriages from couples with recurrent miscarriage: a case-control study. Hum Reprod 17(2):446–451PubMedGoogle Scholar
  103. Su MT, Lin SH, Chen YC (2011) Association of sex hormone receptor gene polymorphisms with recurrent pregnancy loss: a systematic review and meta-analysis. Fertil Steril 96(6):1435–1444PubMedGoogle Scholar
  104. Swierczek SI, Piterkova L, Jelinek J, Agarwal N, Hammoud S, Wilson A, Hickman K, Parker CJ, Cairns B, Prchal JT (2012) Methylation of AR locus does not always reflect X chromosome inactivation state. Blood 119(13):e100–e109PubMedGoogle Scholar
  105. Tanaka M, Kyo S, Kanaya T, Yatabe N, Nakamura M, Maida Y, Okabe M, Inoue M (2003) Evidence of the monoclonal composition of human endometrial epithelial glands and mosaic pattern of clonal distribution in luminal epithelium. Am J Pathol 163(1):295–301PubMedGoogle Scholar
  106. Tomkins DJ, McDonald HL, Farrell SA, Brown CJ (2002) Lack of expression of XIST from a small ring X chromosome containing the XIST locus in a girl with short stature, facial dysmorphism and developmental delay. Eur J Hum Genet 10(1):44–51PubMedGoogle Scholar
  107. Toniolo D, Rizzolio F (2007) X chromosome and ovarian failure. Semin Reprod Med 25(4):264–271PubMedGoogle Scholar
  108. Twigg SR, Kan R, Babbs C, Bochukova EG, Robertson SP, Wall SA, Morriss-Kay GM, Wilkie AO (2004) Mutations of ephrin-B1 (EFNB1), a marker of tissue boundary formation, cause craniofrontonasal syndrome. Proc Natl Acad Sci U S A 101(23):8652–8657PubMedGoogle Scholar
  109. Uehara S, Hashiyada M, Sato K, Sato Y, Fujimori K, Okamura K (2001) Preferential X-chromosome inactivation in women with idiopathic recurrent pregnancy loss. Fertil Steril 76(5):908–914PubMedGoogle Scholar
  110. Uz E, Mustafa C, Topaloglu R, Bilginer Y, Dursun A, Kasapcopur O, Ozen S, Bakkaloglu A, Ozcelik T (2009) Increased frequency of extremely skewed X chromosome inactivation in juvenile idiopathic arthritis. Arthritis Rheum 60(11):3410–3412PubMedGoogle Scholar
  111. van Dijk JP, Heuver LH, van der Reijden BA, Raymakers RA, de Witte T, Jansen JH (2002) A novel, essential control for clonality analysis with human androgen receptor gene polymerase chain reaction. Am J Pathol 161(3):807–812PubMedGoogle Scholar
  112. Van Vlierberghe P, Patel J, Abdel-Wahab O, Lobry C, Hedvat CV, Balbin M, Nicolas C, Payer AR, Fernandez HF, Tallman MS, Paietta E, Melnick A, Vandenberghe P, Speleman F, Aifantis I, Cools J, Levine R, Ferrando A (2011) PHF6 mutations in adult acute myeloid leukemia. Leukemia 25(1):130–134PubMedGoogle Scholar
  113. Vickers MA, McLeod E, Spector TD, Wilson IJ (2001) Assessment of mechanism of acquired skewed X inactivation by analysis of twins. Blood 97(5):1274–1281PubMedGoogle Scholar
  114. Wang X, Reid Sutton V, Omar Peraza-Llanes J, Yu Z, Rosetta R, Kou YC, Eble TN, Patel A, Thaller C, Fang P, Van den Veyver IB (2007) Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia. Nat Genet 39(7):836–838PubMedGoogle Scholar
  115. Wang Y, Busin R, Reeves C, Bezman L, Raymond G, Toomer CJ, Watkins PA, Snowden A, Moser A, Naidu S, Bibat G, Hewson S, Tam K, Clarke JT, Charnas L, Stetten G, Karczeski B, Cutting G, Steinberg S (2011) X-linked adrenoleukodystrophy: ABCD1 de novo mutations and mosaicism. Mol Genet Metab 104(1–2):160–166PubMedGoogle Scholar
  116. Warburton D, Kline J, Kinney A, Yu CY, Levin B, Brown S (2009) Skewed X chromosome inactivation and trisomic spontaneous abortion: no association. Am J Hum Genet 85(2):179–193PubMedGoogle Scholar
  117. Wieacker P, Wieland I (2005) Clinical and genetic aspects of craniofrontonasal syndrome: towards resolving a genetic paradox. Mol Genet Metab 86(1–2):110–116PubMedGoogle Scholar
  118. Xu J, Deng X, Disteche CM (2008a) Sex-specific expression of the X-linked histone demethylase gene Jarid1c in brain. PLoS One 3(7):e2553PubMedGoogle Scholar
  119. Xu J, Deng X, Watkins R, Disteche CM (2008b) Sex-specific differences in expression of histone demethylases Utx and Uty in mouse brain and neurons. J Neurosci 28(17):4521–4527PubMedGoogle Scholar
  120. Yang C, Chapman AG, Kelsey AD, Minks J, Cotton AM, Brown CJ (2011) X-chromosome inactivation: molecular mechanisms from the human perspective. Hum Genet 130(2):175–185PubMedGoogle Scholar
  121. Yang F, Babak T, Shendure J, Disteche CM (2010) Global survey of escape from X inactivation by RNA-sequencing in mouse. Genome Res 20(5):614–622PubMedGoogle Scholar
  122. Yasukochi Y, Maruyama O, Mahajan MC, Padden C, Euskirchen GM, Schulz V, Hirakawa H, Kuhara S, Pan XH, Newburger PE, Snyder M, Weissman SM (2010) X chromosome-wide analyses of genomic DNA methylation states and gene expression in male and female neutrophils. Proc Natl Acad Sci U S A 107(8):3704–3709PubMedGoogle Scholar
  123. Zhang J, Bao X, Cao G, Jiang S, Zhu X, Lu H, Jia L, Pan H, Fehr S, Davis M, Leonard H, Ravine D, Wu X (2011) What does the nature of the MECP2 mutation tell us about parental origin and recurrence risk in Rett syndrome? Clin Genet 82(6):526–533Google Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Wendy P. Robinson
    • 1
    • 2
  • Allison M. Cotton
    • 1
  • Maria S. Peñaherrera
    • 1
    • 2
  • Samantha B. Peeters
    • 1
  • Carolyn J. Brown
    • 1
    Email author
  1. 1.Department of Medical Genetics, Molecular Epigenetics GroupUniversity of British ColumbiaVancouverCanada
  2. 2.Child & Family Research InstituteVancouverCanada

Personalised recommendations