Klinefelter syndrome comorbidities linked to increased X chromosome gene dosage and altered protein interactome activity

In both Turner syndrome (TS) and Klinefelter syndrome (KS) copy number aberrations of the X chromosome lead to various developmental symptoms. We report a comparative analysis of TS vs. KS regarding differences at the genomic network level measured in primary samples by analyzing gene expression, DNA methylation, and chromatin conformation. X-chromosome inactivation (XCI) silences transcription from one X chromosome in female mammals, on which most genes are inactive, and some genes escape from XCI. In TS, almost all differentially expressed escape genes are down-regulated but most differentially expressed inactive genes are up-regulated. In KS, differentially expressed escape genes are up-regulated while the majority of inactive genes appear unchanged. Interestingly, 94 differentially expressed genes (DEGs) overlapped between TS and female and KS and male comparisons; and these almost uniformly display expression changes into opposite directions. DEGs on the X chromosome and the autosomes are coexpressed in both syndromes, indicating that there are molecular ripple effects of the changes in X chromosome dosage. Six potential candidate genes (RPS4X,SEPT6,NKRF,CX0rf57,NAA10, andFLNA) for KS are identified on Xq, as well as candidate central genes on Xp for TS. Only promoters of inactive genes are differentially methylated in both syndromes while escape gene promoters remain unchanged. The intrachromosomal contact map of the X chromosome in TS exhibits the structure of an active X chromosome. The discovery of shared DEGs indicates the existence of common molecular mechanisms for gene regulation in TS and KS that transmit the gene dosage changes to the transcriptome.

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X-chromosome gene dosage as a determinant of impaired pre and postnatal growth and adult height in Turner syndrome

Acta Endocrinologica ◽

10.1530/eje-15-1000 ◽

2016 ◽

Vol 174 (3) ◽

pp. 281-288 ◽

Cited By ~ 9

Author(s):

Elodie Fiot ◽

Delphine Zenaty ◽

Priscilla Boizeau ◽

Jeremy Haigneré ◽

Sophie Dos Santos ◽

...

Keyword(s):

Turner Syndrome ◽

X Chromosome ◽

Multiple Testing ◽

Adult Height ◽

Gene Dosage ◽

Postnatal Growth ◽

Target Height ◽

Anthropometric Parameters ◽

Gh Treatment ◽

Chromosome Gene

ObjectiveShort stature is a key aspect of the phenotype of patients with Turner syndrome (TS). SHOX haploinsufficiency is responsible for about two-thirds of the height deficit. The aim was to investigate the effect of X-chromosome gene dosage on anthropometric parameters at birth, spontaneous height, and adult height (AH) after growth hormone (GH) treatment.DesignWe conducted a national observational multicenter study.MethodsBirth parameter SDS for gestational age, height, and AH before and after GH treatment respectively, and height deficit with respect to target height (SDS) were classified by karyotype subgroup in a cohort of 1501 patients with TS: 45,X (36%), isoXq (19%), 45,X/46,XX (15%), XrX (7%), presence of Y (6%), or other karyotypes (17%).ResultsBirth weight, length (P<0.0001), and head circumference (P<0.001), height and height deficit with respect to target height (SDS) before GH treatment, at a median age of 8.8 (5.3–11.8) years and after adjustment for age and correction for multiple testing (P<0.0001), and AH deficit with respect to target height at a median age of 19.3 (18.0–21.8) years and with additional adjustment for dose and duration of GH treatment (P=0.006), were significantly associated with karyotype subgroup. Growth retardation tended to be more severe in patients with XrX, isoXq, and, to a lesser extent, 45,X karyotypes than in patients with 45,X/46,XX karyotypes or a Y chromosome.ConclusionThese data suggest that haploinsufficiency for an unknown Xp gene increases the risk of fetal and postnatal growth deficit and short AH with respect to target height after GH therapy.

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X-Chromosome Gene Dosage and the Risk of Diabetes in Turner Syndrome

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-0384 ◽

2009 ◽

Vol 94 (9) ◽

pp. 3289-3296 ◽

Cited By ~ 54

Author(s):

Vladimir K. Bakalov ◽

Clara Cheng ◽

Jian Zhou ◽

Carolyn A. Bondy

Keyword(s):

Turner Syndrome ◽

X Chromosome ◽

Gene Dosage ◽

Chromosome Gene

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F.36. The Role of X Chromosome Gene Dosage in Immune Responses

Clinical Immunology ◽

10.1016/j.clim.2009.03.301 ◽

2009 ◽

Vol 131 ◽

pp. S103-S104

Author(s):

Tina Uvebrant ◽

Johan Svensson ◽

Corrado Cilio

Keyword(s):

Immune Responses ◽

X Chromosome ◽

Gene Dosage ◽

Chromosome Gene

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X chromosome gene dosage as a determinant of congenital malformations and of age-related comorbidity risk in patients with Turner syndrome, from childhood to early adulthood

Acta Endocrinologica ◽

10.1530/eje-18-0878 ◽

2019 ◽

Vol 180 (6) ◽

pp. 397-406 ◽

Cited By ~ 3

Author(s):

Elodie Fiot ◽

Delphine Zénaty ◽

Priscilla Boizeau ◽

Jérémie Haignere ◽

Sophie Dos Santos ◽

...

Keyword(s):

Turner Syndrome ◽

X Chromosome ◽

Cumulative Incidence ◽

Congenital Malformations ◽

Gene Dosage ◽

Early Adulthood ◽

Ring Chromosome ◽

Chromosome Gene ◽

Age Related ◽

Design And Methods

ObjectiveTurner Syndrome is associated with several phenotypic conditions associated with a higher risk of subsequent comorbidity. We aimed to evaluate the prevalence of congenital malformations and the occurrence of age-related comorbid conditions and to determine whether the frequencies of congenital and acquired conditions depend on X chromosome gene dosage, as a function of karyotype subgroup.Design and methodsThis national retrospective observational cohort study includes 1501 patients. We evaluated the prevalence of congenital malformations and the cumulative incidence of subsequent specific comorbidities at five-year intervals, from the ages of 10 to 30 years, with stratification by karyotype subgroup: 45,X (n = 549), 45,X/46,isoXq (n = 280), 46,X,r(X)/46,XX (n = 106), 45,X/46,XX (n = 221), presence of Y (n = 87).ResultsMedian age was 9.4 (3.7–13.7) years at first evaluation and 16.8 (11.2–21.4) years at last evaluation. Congenital heart (18.9%) malformations were more frequent in 45,X patients, and congenital renal (17.2%) malformations were more frequent in 45,X, 45,X/46,isoXq and 46,X,r(X)/46,XX patients than in those with 45,X/46,XX mosaicism or a Y chromosome (P < 0.0001). The cumulative incidence of subsequent acquired conditions, such as thyroid disease, hearing loss, overweight/obesity, dyslipidemia and, to a lesser extent, celiac disease, glucose intolerance/type 2 diabetes, hypertension and liver dysfunction increased with age, but less markedly for patients with mosaicism than for those with other karyotypes. Patients with a ring chromosome were more prone to metabolic disorders.ConclusionThese data suggest that X gene chromosome dosage, particularly for Xp genes, contributes to the risk of developing comorbidities.

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X-chromosome gene dosage as a determinant of impaired pre and postnatal growth and adult height in Turner syndrome

Acta Endocrinologica ◽

10.1530/eje-15-1000e ◽

2016 ◽

Vol 175 (3) ◽

pp. X1 ◽

Cited By ~ 1

Author(s):

Elodie Fiot ◽

Delphine Zenaty ◽

Priscilla Boizeau ◽

Jeremy Haigneré ◽

Sophie Dos Santos ◽

...

Keyword(s):

Turner Syndrome ◽

X Chromosome ◽

Adult Height ◽

Gene Dosage ◽

Postnatal Growth ◽

Chromosome Gene

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Escape from X Chromosome Inactivation and the Female Predominance in Autoimmune Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms22031114 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1114

Author(s):

Ali Youness ◽

Charles-Henry Miquel ◽

Jean-Charles Guéry

Keyword(s):

Autoimmune Diseases ◽

X Chromosome ◽

Gene Dosage ◽

X Chromosome Inactivation ◽

Chromosome Inactivation ◽

X Chromosomes ◽

Female Sex Hormones ◽

Inactive X Chromosome ◽

Immune Related Genes ◽

Female Specific

Women represent 80% of people affected by autoimmune diseases. Although, many studies have demonstrated a role for sex hormone receptor signaling, particularly estrogens, in the direct regulation of innate and adaptive components of the immune system, recent data suggest that female sex hormones are not the only cause of the female predisposition to autoimmunity. Besides sex steroid hormones, growing evidence points towards the role of X-linked genetic factors. In female mammals, one of the two X chromosomes is randomly inactivated during embryonic development, resulting in a cellular mosaicism, where about one-half of the cells in a given tissue express either the maternal X chromosome or the paternal one. X chromosome inactivation (XCI) is however not complete and 15 to 23% of genes from the inactive X chromosome (Xi) escape XCI, thereby contributing to the emergence of a female-specific heterogeneous population of cells with bi-allelic expression of some X-linked genes. Although the direct contribution of this genetic mechanism in the female susceptibility to autoimmunity still remains to be established, the cellular mosaicism resulting from XCI escape is likely to create a unique functional plasticity within female immune cells. Here, we review recent findings identifying key immune related genes that escape XCI and the relationship between gene dosage imbalance and functional responsiveness in female cells.

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Detectable chromosome X mosaicism in males is rarely tolerated in peripheral leukocytes

Scientific Reports ◽

10.1038/s41598-020-80948-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Weiyin Zhou ◽

Shu-Hong Lin ◽

Sairah M. Khan ◽

Meredith Yeager ◽

Stephen J. Chanock ◽

...

Keyword(s):

X Chromosome ◽

Gene Dosage ◽

Large Population ◽

Population Based ◽

Chromosome X ◽

Genotyping Array ◽

Chromosome Mosaicism ◽

Age Related ◽

Leukocyte Function ◽

Peripheral Leukocytes

AbstractAge-related male Y and female X chromosome mosaicism is commonly observed in large population-based studies. To investigate the frequency of male X chromosome mosaicism, we scanned for deviations in chromosome X genotyping array intensity data in a population-based survey of 196,219 UK Biobank men. We detected 12 (0.006%) men with mosaic chromosome X gains ≥ 2 Mb and found no evidence for mosaic chromosome X loss, a level of detection substantially lower than for autosomes or other sex chromosomes. The rarity of chromosome X mosaicism in males relative to females reflects the importance of chromosome X gene dosage for leukocyte function.

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