Premature ovarian failure and androgen receptor gene CAG repeat lengths weighted by X chromosome inactivation patterns

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.

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Genetic significance of skewed X-chromosome inactivation in premature ovarian failure

American Journal of Medical Genetics ◽

10.1002/ajmg.a.30256 ◽

2004 ◽

Vol 130A (3) ◽

pp. 240-244 ◽

Cited By ~ 19

Author(s):

Kazuyo Sato ◽

Shigeki Uehara ◽

Masaki Hashiyada ◽

Hiroshi Nabeshima ◽

Jun-ichi Sugawara ◽

...

Keyword(s):

X Chromosome ◽

Premature Ovarian Failure ◽

X Chromosome Inactivation ◽

Ovarian Failure ◽

Chromosome Inactivation ◽

Genetic Significance ◽

Skewed X Chromosome Inactivation

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

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2004-1424 ◽

2004 ◽

Vol 89 (12) ◽

pp. 6208-6217 ◽

Cited By ~ 142

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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