Trial record 4 of 10 for:    Open Studies | "Klinefelter Syndrome"

X-chromosome Inactivation, Epigenetics and the Transcriptome

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2013 by University of Aarhus
Sponsor:
Collaborators:
Lundbeck Foundation
The Korning Foundation Denmark
AP Moeller Foundation
Information provided by (Responsible Party):
University of Aarhus
ClinicalTrials.gov Identifier:
NCT01678261
First received: August 30, 2012
Last updated: December 19, 2013
Last verified: March 2013
  Purpose

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 inactivation/silencing of the X-chromosome is initiated by a gene named Xist-gene (the X inactivation specific transcript).This gene encodes specific structures so called lincRNAs (long intervening specific transcripts) which are very similar to our genetic material (DNA) but which is not coding for proteins. The final result is that women are X-chromosome mosaics with one X-chromosome from the mother and the other X from the father. However, numerous genes on the X-chromosome escape this silencing process by an unknown mechanism. Approximately two third of the genes are silenced, 15 % avoid silencing and 20 percent are silenced or escape depending on the tissue of origin.

The aforementioned long non-protein-coding parts of our genetic material (LincRNAs) are abundant and produced in large quantities but their wole as respect to health and disease need further clarification. Studies indicate that these LincRNAs interact with the protein coding part of our genetic material modifying which genes are translated into proteins and which are not. During this re-modelling there is left foot prints on the genetic material which can indicate if it is a modification that results in silencing or translation of the gene. It is possible to map these foot prints along the entire X-chromosome using molecular techniques like ChIP (Chromatin immunoprecipitation) and ChIP-seq (deep sequencing).

The understanding achieved so far as to the interplay between our genetic material and disease has arisen from genetic syndromes which as the X-chromosome syndromes are relatively frequent and show clear manifestations of disease giving the researcher a possibility to identify genetic material linked to the disease. Turner and Klinefelter syndrome are, as the remaining sex chromosome syndromes, excellent human disease models and can as such help to elaborate on processes contributing to the development of diseases like diabetes, hypothyroidism, main artery dilation and ischemic heart disease.

The purpose of the study is to:

  1. Define the changes in the non-coding part of the X-chromosome.
  2. Identify the transcriptome (non-coding part of the X-chromosome)as respect to the RNA generated from the X-chromosome.
  3. Identify changes in the coding and non-coding parts of the X-chromosome which are specific in relation to Turner syndrome and which can explain the diseases seen in Turner syndrome.
  4. Study tissue affected by disease in order to look for changes in the X-chromosome with respect to both the coding and non-coding part of the chromosome.

6. Determine if certain genes escape X-chromosome silencing and to establish if this is associated with the parent of origin.


Condition
Turner Syndrome
Klinefelter Syndrome
Triple X Syndrome
47 XYY Syndrome
Aortic Aneurysm

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Cross-Sectional
Official Title: X-chromosome Inactivation, Epigenetics and the Transcriptome

Resource links provided by NLM:


Further study details as provided by University of Aarhus:

Primary Outcome Measures:
  • DNA-methylation of CpG-islands. [ Time Frame: Once ] [ Designated as safety issue: No ]
    mapping DNA-methylations of CpG-islands

  • Histone modifications [ Time Frame: Once ] [ Designated as safety issue: No ]
    Permissive and repressive histone modifications on the X-chromosome

  • mRNA and nonRNA [ Time Frame: Once ] [ Designated as safety issue: No ]
    identification of the entire transcriptome including both mRNA and non-coding RNAs (lincRNA as well as miRNA)from the X-chromosome


Biospecimen Retention:   Samples With DNA

Whole blood

Serum

White cells

Tissue


Estimated Enrollment: 395
Study Start Date: September 2012
Estimated Study Completion Date: October 2015
Estimated Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Groups/Cohorts
1a Turner syndrome 45,X
Blood from 50 persons with Turner syndrome an karyotype 45,X
1b Controls for TS 45,X
50 healthy aged female controls matched to the TS 45,X cohort
2a Turner syndrome 45,X mosaics
Blood from 50 persons with Turner syndrome an karyotype 45,X mosaics
2b Controls for TS 45,X mosaics
50 healthy aged female controls matched to the TS 45,X mosaics cohort
3a Paraffin embedded aortic tissue TS
3a Paraffin embedded samples of aortic tissue from 10 persons with TS
3b Paraffin embedded aortic tissue from 10 controls
3b Paraffin embedded samples of aortic tissue from 10 controls who did not die from aortic aneurism
4a 70 47,XXY men
4a Blood from 70 men with Klinefelter syndrome (47,XXY)
4b 70 controls matching group 4a
4b 70 male controls matching group 4a with respect to age.
5a 5 persons with double Y-syndrome
5a Blood from 5 persons with double Y-syndrome (47,XYY)
5b 20 controls matching 5a
5b 20 healthy controls matching group 5a with respect to age
6a 5 persons with triple X-syndrome
6a Blood from 5 persons with triple X-syndrome (47,XXX)
6b 20 controls matching 6a
6b 20 healthy controls matching group 6a with respect to age.
7 10 biological parents of cohort 1a.
7 Blood from 10 biological parents of individuals in cohort 1a

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 80 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Individuals with sex chromosome syndromes will be recruited from out-patient clinics Controls will be recruited from the general population

Criteria

Controls should fore fill the criteria below

Inclusion Criteria:

  • Healthy
  • Age matched

Exclusion Criteria:

  • Any chronic or acute illness thought to influence the outcome measures
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01678261

Contacts
Contact: Christian Trolle, MD +45 6133 9269 Christian.Trolle@ki.au.dk
Contact: Claus H Gravholt, MD +45 7846 9977 claus.gravholt@ki.au.dk

Locations
Denmark
Department of Endocrinology and Internal medicine Recruiting
Aarhus, Denmark, 8000
Contact: Christian Trolle, MD    +45 6133 9269    Christian.Trolle@KI.AU.DK   
Principal Investigator: Christian Trolle, MD         
Sponsors and Collaborators
University of Aarhus
Lundbeck Foundation
The Korning Foundation Denmark
AP Moeller Foundation
Investigators
Study Director: Claus H Gravholt, MD Aarhus University Hospital
Principal Investigator: Christian Trolle, MD Aarhus University Hospital
  More Information

No publications provided

Responsible Party: University of Aarhus
ClinicalTrials.gov Identifier: NCT01678261     History of Changes
Other Study ID Numbers: 19668
Study First Received: August 30, 2012
Last Updated: December 19, 2013
Health Authority: Denmark: Ethics Committee
Denmark: Danish Dataprotection Agency

Keywords provided by University of Aarhus:
Sex chromosome
Turner Syndrome
Klinefelter Syndrome
Triple X Syndrome
47 XYY syndrome
Aortic Aneurysm
Epigenetics
Transcriptome
non-coding RNA

Additional relevant MeSH terms:
Klinefelter Syndrome
Aortic Aneurysm
Aneurysm
Turner Syndrome
Gonadal Dysgenesis
Primary Ovarian Insufficiency
Syndrome
XYY Karyotype
Sex Chromosome Aberrations
Trisomy
Sex Chromosome Disorders of Sex Development
Vascular Diseases
Cardiovascular Diseases
Aortic Diseases
Disorders of Sex Development
Urogenital Abnormalities
Heart Defects, Congenital
Cardiovascular Abnormalities
Heart Diseases
Congenital Abnormalities
Sex Chromosome Disorders
Chromosome Disorders
Genetic Diseases, Inborn
Gonadal Disorders
Endocrine System Diseases
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Disease
Pathologic Processes

ClinicalTrials.gov processed this record on September 16, 2014