Could the Leukocyte X Chromosome Inactivation Pattern Be Extrapolated to Hair Bulbs?

Kaupert, Laura C.; Billerbeck, Ana Elisa C.; Brito, Vinícius Nahime; Mendonca, Berenice B.; Bachega, Tânia A. S. S.

doi:10.1159/000284387

Cited by 4 publications

(5 citation statements)

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“…The X-chromosome inactivation pattern and CAG repeat numbers were determined as previously described [13]. Briefly, PCR amplification of the CAG repeat region of HpaII- digested and undigested samples was carried out using primers flanking the region of interest: 5’-GCTGTGAAGGTTGCTGTTCCTC-3’ and 5'-HEX-GTGCGCGAAGTGATCCAGAA-3’.…”

Section: Methodsmentioning

confidence: 99%

Increased expression of ACTH (MC2R) and androgen (AR) receptors in giant bilateral myelolipomas from patients with congenital adrenal hyperplasia

et al. 2014

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BackgroundAlthough chronic adrenocorticotropic hormone (ACTH) and androgen hyperstimulation are assumed to be involved in the pathogenesis of adrenal myelolipomas associated with poor-compliance patients with congenital adrenal hyperplasia (CAH), the expression of their receptors has not yet been demonstrated in these tumors so far.MethodsWe analyzed Melanocortin 2 receptor (MC2R), Androgen Receptor (AR), Leptin (LEP), and Steroidogenic factor 1 (SF1) expression using real-time qRT-PCR in two giant bilateral adrenal myelolipomas from two untreated simple virilizing CAH cases and in two sporadic adrenal myelolipomas. In addition, the X-chromosome inactivation pattern and CAG repeat numbers in AR exon 1 gene were evaluated in the 4 cases.ResultsThe MC2R gene was overexpressed in myelolipomas from 3 out of 4 patients. AR overexpression was detected in 2 tumors: a giant bilateral myelolipoma in a CAH patient and a sporadic case. Simultaneous overexpression of AR and MC2R genes was found in two of the cases. Interestingly, the bilateral giant myelolipoma associated with CAH that had high androgen and ACTH levels but lacked MC2R and AR overexpression presented a significantly shorter AR allele compared with other tumors. In addition, X-chromosome inactivation pattern analysis showed a polyclonal origin in all tumors, suggesting a stimulatory effect as the trigger for tumor development.ConclusionThese findings are the first evidence for MC2R or AR overexpression in giant bilateral myelolipomas from poor-compliance CAH patients.

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Section: Methodsmentioning

confidence: 99%

Increased expression of ACTH (MC2R) and androgen (AR) receptors in giant bilateral myelolipomas from patients with congenital adrenal hyperplasia

et al. 2014

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“…Contradictory to our results, a previous study analysed XIRs in hair follicles of 21 individuals and found a significant correlation to blood XIR (r=0.67; p=0.009). 25 One possible explanation for this difference is the number of hair follicles used to assay XCI. We used 20 hair follicles, where Kaupert et al used 3–4 follicles to assay XCI.…”

Section: Discussionmentioning

confidence: 99%

Buccal swab as a reliable predictor for X inactivation ratio in inaccessible tissues

et al. 2015

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BackgroundAs a result of the epigenetic phenomenon of X chromosome inactivation (XCI) every woman is a mosaic of cells with either an inactive paternal X chromosome or an inactive maternal X chromosome. The ratio between inactive paternal and maternal X chromosomes is different for every female individual, and can influence an X-encoded trait or disease. A multitude of X linked conditions is known, and for many of them it is recognised that the phenotype in affected female carriers of the causative mutation is modulated by the XCI ratio. To predict disease severity an XCI ratio is usually determined in peripheral blood samples. However, the correlation between XCI ratios in peripheral blood and disease affected tissues, that are often inaccessible, is poorly understood. Here, we tested several tissues obtained from autopsies of 12 female individuals for patch size and XCI ratio.MethodsXCI ratios were analysed using methyl-sensitive PCR-based assays for the AR, PCSK1N and SLITRK4 loci. XCI patch size was analysed by testing the XCI ratio of tissue samples with decreasing size.ResultsXCI patch size was analysed for liver, muscle, ovary and brain samples and was found too small to confound testing for XCI ratio in these tissues. XCI ratios were determined in the easily accessible tissues, blood, buccal epithelium and hair follicle, and compared with ratios in several inaccessible tissues.ConclusionsBuccal epithelium is preferable over peripheral blood for predicting XCI ratios of inaccessible tissues. Ovary is the only inaccessible tissue showing a poor correlation to blood and buccal epithelium, but has a good correlation to hair follicle instead.

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“…The reactions were stopped by incubation at 96°C for 5 min. Both digested and undigested DNA (100 ng) were used for PCR amplifications of the CAG polymorphic tract of the AR gene, as previously described [ 38 , 39 ]. PCR products were submitted to capillary electrophoresis on an ABI PRISM 310 Genetic Analyzer (Applied Biosystems, Foster City, CA USA) and were analyzed by GeneScan software to determine the sizes of the amplified fragments, which were established from their comparisons with size markers submitted to electrophoresis in the same run.…”

Section: Methodsmentioning

confidence: 99%

The Presence of Clitoromegaly in the Nonclassical Form of 21-Hydroxylase Deficiency Could Be Partially Modulated by the CAG Polymorphic Tract of the Androgen Receptor Gene

et al. 2016

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BackgroundIn the nonclassical form (NC), good correlation has been observed between genotypes and 17OH-progesterone (17-OHP) levels. However, this correlation was not identified with regard to the severity of hyperandrogenic manifestations, which could depend on interindividual variability in peripheral androgen sensitivity. Androgen action is modulated by the polymorphic CAG tract (nCAG) of the androgen receptor (AR) gene and by polymorphisms in 5α-reductase type 2 (SRD5A2) enzyme, both of which are involved in the severity of hyperandrogenic disorders.ObjectivesTo analyze whether nCAG-AR and SRD5A2 polymorphisms influence the severity of the nonclassical phenotype.PatientsNC patients (n = 114) diagnosed by stimulated-17OHP ≥10 ng/mL were divided into groups according to the beginning of hyperandrogenic manifestations (pediatric and adolescent/adult) and CYP21A2 genotypes (C/C: homozygosis for mild mutations; A/C: compound heterozygosis for severe/mild mutations).MethodsCYP21A2 mutations were screened by allelic-specific PCR, MLPA and/or sequencing. HpaII-digested and HpaII-undigested DNA samples underwent GeneScan analysis to study nCAG, and the SRD5A2 polymorphisms were screened by RLFP.ResultsMean nCAG did not differ among pediatric, adolescent/adult and asymptomatic subjects. In the C/C genotype, we observed a significantly lower frequency of longer CAG alleles in pediatric patients than in adolescent/adults (p = 0.01). In patients carrying the A/C genotype, the frequencies of shorter and longer CAG alleles did not differ between pediatric patients and adolescent/adults (p>0.05). Patients with clitoromegaly had significantly lower weighted CAG biallelic mean than those without it: 19.1±2.7 and 21.6±2.5, respectively (p = 0.007), independent of the CYP21A2 genotype's severity. The SRD5A2 polymorphisms were not associated with the variability of hyperandrogenic NC phenotypes.ConclusionsIn this series, we observed a modulatory effect of the CAG-AR tract on clinical manifestations of the NC form. Although the NC form is a monogenic disorder, our preliminary data suggested that the interindividual variability of the hyperandrogenic phenotype could arise from polygenic interactions.

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Could the Leukocyte X Chromosome Inactivation Pattern Be Extrapolated to Hair Bulbs?

Cited by 4 publications

References 58 publications

Increased expression of ACTH (MC2R) and androgen (AR) receptors in giant bilateral myelolipomas from patients with congenital adrenal hyperplasia

Increased expression of ACTH (MC2R) and androgen (AR) receptors in giant bilateral myelolipomas from patients with congenital adrenal hyperplasia

Buccal swab as a reliable predictor for X inactivation ratio in inaccessible tissues

The Presence of Clitoromegaly in the Nonclassical Form of 21-Hydroxylase Deficiency Could Be Partially Modulated by the CAG Polymorphic Tract of the Androgen Receptor Gene

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