X Chromosome Inactivation Pattern is not Associated With Interindividual Variations in Thyroid Volume: A Study of Euthyroid Danish Female Twins

2009 ◽  
Vol 12 (5) ◽  
pp. 502-506 ◽  
Author(s):  
Thomas Heiberg Brix ◽  
Pia Skov Hansen ◽  
Finn Noe Bennedbæk ◽  
Steen Joop Bonnema ◽  
Kirsten Ohm Kyvik ◽  
...  
Keyword(s):  
X Chromosome ◽  
Twin Pair ◽  
Receptor Gene ◽  
Thyroid Volume ◽  
X Chromosome Inactivation ◽  
Cag Repeat ◽  
Chromosome Inactivation ◽  
Pcr Analysis ◽  
Autoimmune Thyroid ◽  
The Impact

AbstractAhigher frequency of skewed X chromosome inactivation (XCI) is found in patients with autoimmune thyroid disease (AITD) than in controls. Although goitre is often present in AITD, a recent study failed to show an association between XCI and clinically overt nontoxic goitre. However, the etiology of overt goitre is complex, and the mechanisms influencing thyroid volume may involve fewer factors than the mechanisms underlying overt goitre. In order to examine the impact of XCI on thyroid volume in euthyroid females, we studied whether within cohort (n= 138) and within twin pair (n= 69) differences in XCI are correlated with differences in thyroid volume. XCI was determined by PCR analysis of a polymorphic CAG repeat in the first exon of the androgen receptor gene. Thyroid volume was determined by ultrasound. Neither in the within cohort nor in the within twin pair analysis could we demonstrate a statistically significant association between XCI and thyroid volume: Regression coefficient (β) = 0.023 (95% confidence interval, –0.062–0.108),p= 0.592 and β = 0.038 (–0.080–0.156),p= 0.521, respectively. Controlling for potential confounders such as zygosity, age, TSH, smoking habits and use of oral contraceptives did not change the findings. In conclusion, in a sample of euthyroid Danish female twins, we found no evidence of a relationship between XCI pattern and thyroid volume.

scholarly journals Molecular Mechanisms of Skewed X-Chromosome Inactivation in Female Hemophilia Patients—Lessons from Wide Genome Analyses

2021 ◽  
Vol 22 (16) ◽  
pp. 9074
Author(s):  
Rima Dardik ◽  
Einat Avishai ◽  
Shadan Lalezari ◽  
Assaf A. Barg ◽  
Sarina Levy-Mendelovich ◽  
...  
Keyword(s):  
X Chromosome ◽  
Molecular Mechanisms ◽  
Gene Mutations ◽  
Bioinformatic Analysis ◽  
Pathogenic Mutation ◽  
X Chromosome Inactivation ◽  
Cag Repeat ◽  
Chromosome Inactivation ◽  
Pcr Analysis ◽  
Two Generations

Introduction: Hemophilia A (HA) is an X-linked bleeding disorder caused by factor VIII (FVIII) deficiency or dysfunction due to F8 gene mutations. HA carriers are usually asymptomatic because their FVIII levels correspond to approximately half of the concentration found in healthy individuals. However, in rare cases, a carrier may exhibit symptoms of moderate to severe HA primarily due to skewed inactivation of her non-hemophilic X chromosome. Aim: The aim of the study was to investigate X-chromosome inactivation (XCI) patterns in HA carriers, with special emphasis on three karyotypically normal HA carriers presenting with moderate to severe HA phenotype due to skewed XCI, in an attempt to elucidate the molecular mechanism underlying skewed XCI in these symptomatic HA carriers. The study was based on the hypothesis that the presence of a pathogenic mutation on the non-hemophilic X chromosome is the cause of extreme inactivation of that X chromosome. Methods: XCI patterns were studied by PCR analysis of the CAG repeat region in the HUMARA gene. HA carriers that demonstrated skewed XCI were further studied by whole-exome sequencing (WES) followed by X chromosome-targeted bioinformatic analysis. Results: All three HA carriers presenting with the moderate to severe HA phenotype due to skewed XCI were found to carry pathogenic mutations on their non-hemophilic X chromosomes. Patient 1 was diagnosed with a frameshift mutation in the PGK1 gene that was associated with familial XCI skewing in three generations. Patient 2 was diagnosed with a missense mutation in the SYTL4 gene that was associated with familial XCI skewing in two generations. Patient 3 was diagnosed with a nonsense mutation in the NKAP gene that was associated with familial XCI skewing in two generations. Conclusion: Our results indicate that the main reason for skewed XCI in our female HA patients was negative selection against cells with a disadvantage caused by an additional deleterious mutation on the silenced X chromosome, thus complicating the phenotype of a monogenic X-linked disease. Based on our study, we are currently offering the X inactivation test to symptomatic hemophilia carriers and plan to expand this approach to symptomatic carriers of other X-linked diseases, which can be further used in pregnancy planning.

scholarly journals Androgen Receptor Gene CAG Repeat Polymorphism and X-Chromosome Inactivation in Children with Premature Adrenarche

2008 ◽  
Vol 93 (4) ◽  
pp. 1304-1309 ◽  
Author(s):  
Saila Lappalainen ◽  
Pauliina Utriainen ◽  
Tiina Kuulasmaa ◽  
Raimo Voutilainen ◽  
Jarmo Jääskeläinen
Keyword(s):  
Androgen Receptor ◽  
X Chromosome ◽  
Receptor Gene ◽  
X Chromosome Inactivation ◽  
Cag Repeat ◽  
Chromosome Inactivation ◽  
University Hospital ◽  
Healthy Children ◽  
Adrenal Androgen ◽  
Premature Adrenarche

Abstract Context: There is variation in the adrenal androgen levels and clinical findings of children with premature adrenarche (PA). Objectives: We hypothesized that androgen sensitivity, indicated by the length of CAG repeat in the X-chromosomal androgen receptor (AR) gene has a role in the polygenic pathogenesis of PA. Design and Patients: We performed a cross-sectional association study among 73 Finnish Caucasian children with PA (10 boys and 63 girls) and 97 age- and gender-matched healthy controls (18 boys and 79 girls). Main Outcome Measures: AR gene methylation-weighted CAGn(mwCAGn) via CAGn length and X-chromosome inactivation analysis and clinical phenotype were determined. Setting: The study took place at a university hospital. Results: PA subjects had significantly shorter mwCAGn than controls [mean difference (95% confidence interval); 0.76 (0.14–1.38); P = 0.017]. AR gene mwCAGn did not correlate with androgen or SHBG levels in either group. In children with PA, mwCAGn correlated positively with body mass index (BMI) (τ = 0.19; P = 0.02). The mean of mwCAGn was significantly shorter in PA children with lower BMI compared with PA children with higher BMI [BMI sd score < 0.79, n = 35, vs. BMI sd score > 0.79, n = 36; 1.13 (0.38–1.87), P = 0.004] and in PA children with lower BMI compared with healthy children with same BMI (P = 0.004). Conclusions: The AR gene CAGn polymorphism may have a significant role in the pathogenesis of PA, especially in lean children.

Functional analysis of ectodysplasin-A mutations and involvement of X-chromosome inactivation

2021 ◽  
Author(s):  
Yuhua Pan ◽  
Ting Lu ◽  
Ling Peng ◽  
Qi Zeng ◽  
Xiangyu Huang ◽  
...  
Keyword(s):  
Functional Analysis ◽  
X Chromosome ◽  
Pcr Amplification ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Tooth Agenesis ◽  
Human Dental Pulp ◽  
Underlying Mechanisms ◽  
The Impact ◽  
Female Carriers

Abstract Objectives: The aim of this study was to identify genetic clues for the causes of familial non-syndromic oligodontia and explore the underlying mechanisms involved, while focusing on the role of human dental pulp stem cells (hDPSCs).Materials and Methods: Candidate gene sequences were obtained by PCR amplification and Sanger sequencing. Functional analysis was conducted, and the pathogenesis associated with EDA mutations in hDPSCs was investigated to explore the impact of the identified mutation on the phenotype. Capillary electrophoresis (CE) was used to detect X chromosome inactivation (XCI) in the blood of female carriers.Results: In this study, we identified an EDA mutation in a Chinese family：the missense mutation c.1013C>T (Thr338Met). Transfection of hDPSCs with a mutant EDA lentivirus decreased the expression of EDA and dentin sialophosphoprotein (DSPP) compared with transfection of control EDA lentivirus. Mechanistically, mutant EDA inhibited the activation of the NF-κB pathway. The CE results showed that symptomatic female carriers had a skewed XCI with a preferential inactivation of the X chromosome that carried the normal allele.Conclusions: In summary, we demonstrated that EDA mutations result in non-syndromic tooth agenesis in heterozygous females and that, mechanistically, EDA regulates odontogenesis through the NF-κB signalling pathway in hDPSCs.Clinical Relevance: Due to the large heterogeneity of tooth agenesis, this study provided a genetic basis for individuals who exhibit similar clinical phenotypes.

scholarly journals X-Chromosome Inactivation Patterns and Androgen Receptor Functionality Influence Phenotype and Social Characteristics as Well as Pharmacogenetics of Testosterone Therapy in Klinefelter Patients

2004 ◽  
Vol 89 (12) ◽  
pp. 6208-6217 ◽  
Author(s):  
Michael Zitzmann ◽  
Marion Depenbusch ◽  
Jörg Gromoll ◽  
Eberhard Nieschlag
Keyword(s):  
Androgen Receptor ◽  
X Chromosome ◽  
Body Height ◽  
X Chromosome Inactivation ◽  
Cag Repeat ◽  
Chromosome Inactivation ◽  
Social Characteristics ◽  
Social Traits ◽  
Arm Span ◽  
Androgen Effects

Abstract Klinefelter syndrome is characterized by a vast range of phenotypes related to androgen effects. Testosterone (T) acts via the X-linked androgen receptor gene carrying the CAG repeat (CAGn) polymorphism, the length of which is inversely associated with androgen action and might account for the marked variation in phenotypes. In 77 newly diagnosed and untreated Klinefelter patients with a 47,XXY karyotype we assessed phenotype and social traits in relation to X-weighted biallelic CAGn length using X-chromosome inactivation analysis after digestion of leukocyte DNA with methylation-sensitive HpaII. Forty-eight men were hypogonadal and received T substitution therapy; in these, pharmacogenetic effects were investigated. The shorter CAGn allele was preferentially inactive. CAGn length was positively associated with body height. Bone density and the relation of arm span to body height were inversely related to CAGn length. The presence of long CAGn was predictive for gynecomastia and smaller testes, whereas short CAGn were associated with a stable partnership and professions requiring higher standards of education also when corrected for family background. There was a trend for men with longer CAGn to be diagnosed earlier in life. Under T substitution, men with shorter CAGn exhibited a more profound suppression of LH levels, augmented prostate growth, and higher hemoglobin concentrations. A significant genotype-phenotype association exists in Klinefelter patients: androgen effects on appearance and social characteristics are modulated by the androgen receptor CAGn polymorphism. The effects of T substitution are pharmacogenetically modified. This finding is magnified by preferential inactivation of the more functional short CAGn allele.

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