Clinical Trial: X-chromosome Inactivation, Epigenetics and the Transcriptome

Study Status: Completed
Recruit Status: Completed
Study Type: Observational

Official Title: X-chromosome Inactivation, Epigenetics and the Transcriptome

Brief Summary:

The human genetic material consists of 46 chromosomes of which two are sex chromosomes. The sex-chromosome from the mother is the X and from the father the Y-chromosome. Hence a male consist of one Y and one X chromosome and a female of 2 X-chromosomes. Alterations in the number of sex-chromosomes and in particular the X-chromosome is fundamental to the development of numerous syndromes such as Turner syndrome (45,X), Klinefelter syndrome (47,XXY), triple X syndrome (47,XXX) and double Y syndrome (47,XYY). Despite the obvious association between the X-chromosome and disease only one gene has been shown to be of significance, namely the short stature homeobox gene (SHOX). Turner syndrome is the most well characterized and the typical diseases affecting the syndrome are:

  • An Increased risk of diseases where one's own immune system reacts against one's own body (autoimmune diseases) and where the cause of this is not known; For example diabetes and hypothyroidism.
  • Increased risk of abortion and death in uteri
  • Underdeveloped ovaries with the inability to produce sex hormones and being infertile.
  • Congenital malformations of the major arteries and the heart of unknown origin.
  • Alterations in the development of the brain, especially with respect to the social and cognitive dimensions.
  • Increased incidence obesity, hypertension, diabetes and osteoporosis.

In healthy women with to normal X-chromosomes, the one of the X-chromosomes is switched off (silenced). The X-chromosome which is silenced varies from cell to cell. The silencing is controlled by a part of the X-chromosome designated XIC (X-inactivation center). The inacti

Detailed Summary:

The X chromosome is a cornerstone to the pathogenesis of a number of syndromes, whereof some are Turner syndrome (45,X), Klinefelter syndrome (47,XXY), triple X syndrome (47,XXX) and double Y syndrome (47,XYY). Despite this importance to clinical disease, only one gene on the X chromosome has so far been implicated in the wide spectra of phenotypic traits seen in these and other X-related syndromes. The one known gene is the SHOX (the short stature homeobox) gene and encodes a transcription factor that has brain natriuretic peptide (BNP) and fibroblast growth factor receptor gene (FGFR3) as transcriptional targets. It is located at the pseudoautosomal region of the X and Y chromosomes. This gene has been shown to be involved in short stature in Turner syndrome, Leri-Weill syndrome and idiopathic short stature. It also causes the increased stature in Klinefelter syndrome, triple X syndrome and XYY syndrome.

A number of traits and diseases are seen frequently in X-chromosomal syndromes that cannot be explained by this SHOX gene. The best characterized of these syndromes is Turner syndrome, where these phenotype traits can be divided into:

  1. Autoimmune predilection, which leads to an increased risk of virtually all autoimmune diseases of unknown pathogenesis such as diabetes and hypothyroidism.
  2. Decreased intrauterine viability. Here haploinsufficiency of X-linked pseudoautosomal genes operating in the placenta has been suggested to be involved (STS and CSF2RA).
  3. Ovarian dysgenesis, leading to ovarian insufficiency and the need for long term sex hormone replacement therapy.
  4. Congenital cardiovascular malformations of unresolved pathogeneses.
  5. Brain development, e
    Sponsor: University of Aarhus

    Current Primary Outcome:

    • DNA-methylation of CpG-islands. [ Time Frame: Once ]
      mapping DNA-methylations of CpG-islands
    • Histone modifications [ Time Frame: Once ]
      Permissive and repressive histone modifications on the X-chromosome
    • mRNA and nonRNA [ Time Frame: Once ]
      identification of the entire transcriptome including both mRNA and non-coding RNAs (lincRNA as well as miRNA)from the X-chromosome


    Original Primary Outcome: Same as current

    Current Secondary Outcome:

    Original Secondary Outcome:

    Information By: University of Aarhus

    Dates:
    Date Received: August 30, 2012
    Date Started: September 2012
    Date Completion:
    Last Updated: May 23, 2016
    Last Verified: June 2015