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X-chromosome inactivation: implications in human disease

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Abstract

X-chromosome inactivation (XCI) is a process involved in the pathogenesis of several diseases. In this mini review, we discuss the known mechanisms associated with XCI, when and how does it initiate, spreads and maintain, as well as the mechanisms that allow some genes to escape from it. We address the skewed XCI, condition in which the process are not fully randomized and its consequences to the phenotype of some pathologies. We debate about the known pathologies implicated, including X unbalanced rearrangements, X-autosomal balanced translocations, Turner and Klinefelter syndromes and also for X-linked diseases and its consequences in males and females. Some pathologies are discussed more in detail such as intellectual disability with a recognized relationship with XCI. Finally, possible future implications of genomic therapy and treatment of patients and list of areas that need further research on this topic are addressed.

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References

  • Aarabi M., Kessler E., Madan-Khetarpal S., Surti U., Bellissimo D., Rajkovic A. et al. 2019 Autism spectrum disorder in females with ARHGEF9 alterations and a random pattern of X chromosome inactivation. Eur. J. Med. Genet. 62, 239–242.

    Article  Google Scholar 

  • Berletch J. B., Yang F., Xu J., Carrel L. and Disteche C. M. 2011 Genes that escape from X inactivation. Hum. Genet. 130, 237–245.

    Article  Google Scholar 

  • Bicocchi M. P., Migeon B. R., Pasino M., Lanza T., Bottini F., Boeri E. et al. 2005 Familial nonrandom inactivation linked to the X inactivation centre in heterozygotes manifesting haemophilia A. Eur. J. Hum. Genet. 13, 635–640.

    Article  CAS  Google Scholar 

  • Blaschke R. J. and Rappold G. 2006 The pseudoautosomal regions, SHOX and disease. Curr. Opin. Genet. Dev. 16, 233–239.

    Article  CAS  Google Scholar 

  • Cantone I. and Fisher A. G. 2017 Human X chromosome inactivation and reactivation: implications for cell reprogramming and disease. Philos. Trans. R. Soc. London B Biol. Sci. 372, 20160358.

    Article  Google Scholar 

  • Disteche C. and Berletch J. 2015 X-chromosome Inactivation and Escape. J. Genet. 94, 591–598.

    Article  Google Scholar 

  • Disteche C. 2016 Dosage compensation of the sex chromosomes and autosomes. Semin. Cell Dev. Biol. 56, 9–18.

    Article  CAS  Google Scholar 

  • Dixon-McDougall T. and Brown C. 2016 The making of a Barr body: the mosaic of factors that eXIST on the mammalian inactive X chromosome. Biochem. Cell Biol. 94, 56–70.

    Article  CAS  Google Scholar 

  • Echevarria L., Benistan K., Toussaint A., Dubourg O., Hagege A. A., Eladari D. et al. 2016 X-chromosome inactivation in female patients with Fabry disease. Clin. Genet. 89, 44–54.

    Article  CAS  Google Scholar 

  • Engreitz J. M., Pandya-Jones A., McDonel P., Shishkin A., Sirokman K., Surka C. et al. 2013 The Xist lncRNA exploits three-dimensional genome architecture to spread across the X chromosome. Science 341, 1237973.

    Article  Google Scholar 

  • Fang H., Disteche C. and Berletch J. 2019 X inactivation and escape: epigenetic and structural features. Front. Cell Dev. Biol. 7, 219.

    Article  Google Scholar 

  • Galupa R. and Heard E. 2018 X-chromosome inactivation: a crossroads between chromosome architecture and gene regulation. Annu. Rev. Genet. 52, 535–566.

    Article  CAS  Google Scholar 

  • Gieldon L., Mackenroth L., Betcheva-Krajcir E., Rump A., Beck-Wödl S., Schallner J. et al. 2017 Skewed X-inactivation in a family with DLG3-associated X-linked intellectual disability. Am. J. Med. Genet. A 173, 2545–2550.

    Article  CAS  Google Scholar 

  • Halmai J. A. N. M., Deng P., Gonzalez C. E., Coggins N. B., Cameron D., Carter J. L. et al. 2020 Artificial escape from XCI by DNA methylation editing of the CDKL5 gene. Nuclic Acids Res. 48, 2372–2387.

    Article  CAS  Google Scholar 

  • Jiang J., Jing Y., Cost G. J., Chiang J. C., Kolpa H. J., Cotton A. M. et al. 2013 Translating dosage compensation to trisomy 21. Nature 500, 296–300.

    Article  CAS  Google Scholar 

  • Leppig K. A. and Disteche C. M. 2001 Ring X and other structural X chromosome abnormalities: X inactivation and phenotype. Semin. Reprod. Med. 19, 147–157.

    Article  CAS  Google Scholar 

  • Mattei M. G., Mattei J. F., Ayme S. and Giraud F. 1982 X-autosome translocations: cytogenetic characteristics and their consequences. Hum. Genet. 61, 295–309.

    Article  CAS  Google Scholar 

  • Monk M., Boubelik M. and Lehnert S. 1987 Temporal and regional changes in DNA methylation in the embryonic, extraembryonic and germ cell lineages during mouse embryo development. Development 99, 371–382.

    Article  CAS  Google Scholar 

  • Monkhorst K., Jonkers I., Rentmeester E., Grosveld F. and Gribnau J. 2008 X inactivation counting and choice is a stochastic process: evidence for involvement of an X-linked activator. Cell 132, 410–421.

    Article  CAS  Google Scholar 

  • Payer B. 2016 Developmental regulation of X-chromosome inactivation. Semin. Cell Dev. Biol. 56, 88–99.

    Article  CAS  Google Scholar 

  • Pinter S. F., Sadreyev R. I., Yildirim E., Jeon Y., Ohsumi T. K. and Borowsky M. 2012 Spreading of X chromosome inactivation via a hierarchy of defined Polycomb stations. Genome. Res. 22, 1864–1876.

    Article  CAS  Google Scholar 

  • Plenge R. M., Stevenson R. A., Lubs H. A., Schwartz C. E. and Willard H. F. 2002 Skewed X-chromosome inactivation is a common feature of X-linked mental retardation disorders. Am. J. Hum. Genet. 71, 168–173.

    Article  CAS  Google Scholar 

  • Posynick B. J. and Brown C. J. 2019 Escape from X-chromosome inactivation: an evolutionary perspective. Front. Cell Dev. Biol. 7, 241.

    Article  Google Scholar 

  • Sierra I. and Anguera M. C. 2019 Enjoy the silence: X-chromosome inactivation diversity in somatic cells. Curr. Opin. Genet. Dev. 55, 26–31.

    Article  CAS  Google Scholar 

  • Shoukat H. M. H., Ghous G., Tarar Z. I., Shoukat M. M. and Ajmal N. 2020 Skewed inactivation of X chromosome: a cause of Hemophilia manifestation in carrier females. Cureus 12, e11216.

    PubMed  PubMed Central  Google Scholar 

  • Sun Y., Luo Y., Qian Y., Chen M., Wang L., Li H. et al. 2019 Heterozygous deletion of the SHOX gene enhancer in two females with clinical heterogeneity associating with skewed XCI and escaping XCI. Front. Genet. 10, 1086.

    Article  Google Scholar 

  • Yamoto K., Saitsu H., Fujisawa Y., Kato F., Matsubara K., Fukami M. et al. 2020 Coffin-Lowry syndrome in a girl with 46, XX, t(X;11)(p22;p15)dn: Identification of RPS6KA3 disruption by whole genome sequencing. Clin. Case Rep. 8, 1076–1080.

    Article  Google Scholar 

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Author notes

  1. Guilherme Pereira was responsible for the literature review, drafting and revision of the paper. Sofia Dória was responsible for the critical revision and for the final manuscript editing.

Authors and Affiliations

  1. Faculty of Medicine, University of Porto, Porto, Portugal

    Guilherme Pereira

  2. Genetics Service, Faculty of Medicine, Department of Pathology, University of Porto, Porto, Portugal

    Sofia Dória

  3. I3S - Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal

    Sofia Dória

Authors
  1. Guilherme Pereira
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  2. Sofia Dória
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Correspondence to Sofia Dória.

Additional information

Corresponding editor: Durgadas P. Kasbekar.

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Pereira, G., Dória, S. X-chromosome inactivation: implications in human disease. J Genet 100, 63 (2021). https://doi.org/10.1007/s12041-021-01314-1

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  • DOI: https://doi.org/10.1007/s12041-021-01314-1

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