X-chromosome Inactivation, Epigenetics and the Transcriptome

NCT01678261 | Completed

• 1 other identifier: 19668
• Study Type: observational
• Target: 110
• Locations: 1 country
• Sites: 1

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 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:
• Define the changes in the non-coding part of the X-chromosome.
• Identify the transcriptome (non-coding part of the X-chromosome)as respect to the RNA generated from the X-chromosome.
• 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.
• 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.

Conditions

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

Keywords

Sex chromosome; Turner Syndrome; Klinefelter Syndrome; Triple X Syndrome; 47 XYY syndrome; Aortic Aneurysm; Epigenetics; Transcriptome; non-coding RNA

Outcome Measures

Primary Outcomes (3)

• DNA-methylation of CpG-islands.

  mapping DNA-methylations of CpG-islands

  Once

• Histone modifications

  Permissive and repressive histone modifications on the X-chromosome

  Once

• mRNA and nonRNA

  identification of the entire transcriptome including both mRNA and non-coding RNAs (lincRNA as well as miRNA)from the X-chromosome

  Once

Study Arms (13)

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

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• 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

You may qualify if:

• Healthy
• Age matched

You may not qualify if:

• Any chronic or acute illness thought to influence the outcome measures

Sponsors & Collaborators

• University of Aarhus: lead
• Lundbeck Foundation: collaborator
• The Korning Foundation Denmark: collaborator
• AP Moeller Foundation: collaborator

Study Sites (1)

Department of Endocrinology and Internal medicine

Aarhus, 8000, Denmark

Location

Related Publications (2)

• Viuff M, Skakkebaek A, Johannsen EB, Chang S, Pedersen SB, Lauritsen KM, Pedersen MGB, Trolle C, Just J, Gravholt CH. X chromosome dosage and the genetic impact across human tissues. Genome Med. 2023 Mar 28;15(1):21. doi: 10.1186/s13073-023-01169-4.

  PMID: 36978128 DERIVED

• Funck KL, Budde RPJ, Viuff MH, Wen J, Jensen JM, Norgaard BL, Bons LR, Duijnhouwer AL, Dey D, Mortensen KH, Andersen NH, Roos-Hesselink JW, Gravholt CH. Coronary plaque burden in Turner syndrome a coronary computed tomography angiography study. Heart Vessels. 2021 Jan;36(1):14-23. doi: 10.1007/s00380-020-01660-7. Epub 2020 Jul 1.

  PMID: 32613319 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Whole blood Serum White cells Tissue

MeSH Terms

Conditions

Turner Syndrome; Klinefelter Syndrome; Triple X syndrome; 47, XYY syndrome; Aortic Aneurysm

Condition Hierarchy (Ancestors)

Gonadal Dysgenesis; Disorders of Sex Development; Urogenital Abnormalities; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Sex Chromosome Disorders of Sex Development; Male Urogenital Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Sex Chromosome Disorders; Chromosome Disorders; Genetic Diseases, Inborn; Gonadal Disorders; Endocrine System Diseases; Hypogonadism; Aneurysm; Vascular Diseases; Aortic Diseases

Study Officials

• Claus H Gravholt, MD

  Aarhus University Hospital

  STUDY DIRECTOR

• Christian Trolle, MD

  Aarhus University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 30, 2012
• First Posted: September 3, 2012
• Study Start: September 1, 2012
• Primary Completion: October 1, 2015
• Study Completion: January 1, 2016
• Last Updated: May 24, 2016

Record last verified: 2015-06

Locations

DK (1)