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.

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.

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 Bone Mass in Subjects with Klinefelter Syndrome: Role of Testosterone Levels and Androgen Receptor Gene CAG Polymorphism

2011 ◽  
Vol 96 (4) ◽  
pp. E739-E745 ◽  
Author(s):  
Alberto Ferlin ◽  
Mirko Schipilliti ◽  
Cinzia Vinanzi ◽  
Andrea Garolla ◽  
Antonella Di Mambro ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Bone Mass ◽  
X Chromosome ◽  
Klinefelter Syndrome ◽  
X Chromosome Inactivation ◽  
Cag Repeat ◽  
Low Bone Mass ◽  
Testosterone Levels ◽  
Cag Polymorphism ◽  
Low Testosterone

Abstract Context: Klinefelter syndrome (KS) is a chromosomal alteration characterized by supernumerary X-chromosome(s), primary hypogonadism, decreased pubertal peak bone mineral density (BMD), and accelerated bone loss during adulthood. Decreased bone mass has been traditionally related to low testosterone levels. However, testosterone replacement therapy does not necessarily increase bone mass in these patients, and low BMD can be observed also in patients with normal testosterone levels. The androgen receptor (AR) gene CAG polymorphism seems to modulate the sensitivity to testosterone and previous studies have related it to some clinical aspects of KS, to include BMD, gynecomastia, testes and prostate volume, and hemoglobin concentration. Objective: To analyze the relation between bone mass, testosterone, and AR CAG polymorphism in men with KS. Design: Cross-sectional cohort study. Setting: University department. Patients: One hundred twelve consecutive treatment-naïve 47,XXY Klinefelter patients (mean age 33.5 ± 4.7 yr) and 51 age-matched normal male controls. Main Outcome Measures: Dual-energy x-ray absorptiometry, CAG repeat length polymorphism, X-chromosome inactivation, and testosterone levels. Results: Forty-nine of 112 KS subjects (42.5%) had low bone mass (osteopenia or osteoporosis). Lumbar and/or femoral T-scores were lower in KS patients compared with controls. No significant relationship was observed between testosterone levels and bone parameters, and the prevalence of osteopenia/osteoporosis was similar in subjects with normal and low testosterone levels (43.7% and 40.5%, respectively). The mean CAG repeat length calculated after X-chromosome inactivation analysis showed no differences between patients with normal and low bone mass. Conclusions: Testosterone levels and AR CAG polymorphism are not associated with bone mass phenotype in KS.

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