Extremely Skewed X-Chromosome Inactivation Is Increased in Women with Recurrent Spontaneous Abortion

Sangha, Karan; Stephenson, Mary D.; Brown, Carolyn J.; Robinson, Wendy P.

doi:10.1086/302552

Cited by 77 publications

(81 citation statements)

References 28 publications

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“…The pedigrees of many AITDs probands with skewed XCI versus those with random XCI were interesting in two aspects. First, recurrent spontaneous abortions (defined as three or more pregnancy losses), which have been shown to be associated with skewed XCI, 16,18 occurred in four of 25 (16%) of our AITDs probands with skewed XCI. Conversely, a history of recurrent spontaneous abortions was negative both in the patients with random XCI and in the control group subjects (Po0.0199).…”

Section: Resultsmentioning

confidence: 93%

“…It has been reported in only 1 -2% of women aged 20 -40 years, and in 2 -4% of women aged 55 -72 years. 15,16 The distribution of XCI skewing in the general population is thought to be mainly due to chance deviations from 50:50 as a result of the limited number of embryonic cells present (4 -20) at the time of XCI. 17 Age alone is unlikely to influence the strikingly bimodal data in our AITDs patients ( Figure 1).…”

Section: Resultsmentioning

confidence: 99%

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Evidence from autoimmune thyroiditis of skewed X-chromosome inactivation in female predisposition to autoimmunity

et al. 2006

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The etiologic factors in the development of autoimmune thyroid diseases (AITDs) are not fully understood. We investigated the role of skewed X-chromosome inactivation (XCI) mosaicism in female predisposition to AITDs. One hundred and ten female AITDs patients (81 Hashimoto's thyroiditis (HT), 29 Graves' disease (GD)), and 160 female controls were analyzed for the androgen receptor locus by the HpaII/polymerase chain reaction assay to assess XCI patterns in DNA extracted from peripheral blood cells. In addition, thyroid biopsy, buccal mucosa, and hair follicle specimens were obtained from five patients whose blood revealed an extremely skewed pattern of XCI, and the analysis was repeated. Skewed XCI was observed in DNA from peripheral blood cells in 28 of 83 informative patients (34%) as compared with 10 of 124 informative controls (8%, Po0.0001). Extreme skewing was present in 16 patients (19%), but only in three controls (2.4%, Po0.0001). The buccal mucosa, and although less marked, the thyroid specimens also showed skewing. Analysis of two familial cases showed that only the affected individuals demonstrate skewed XCI patterns. Based on these results, skewed XCI mosaicism may play a significant role in the pathogenesis of AITDs.

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Evidence from autoimmune thyroiditis of skewed X-chromosome inactivation in female predisposition to autoimmunity

et al. 2006

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“…To achieve this, Xlinked genes with known nucleotide polymorphisms have been utilized, including a BstXI site polymorphism in intron 1 of the phosphoglycerate kinase (PGK) gene and a CAG triplet repeat [(CAG)n] polymorphism in exon 1 of the androgen receptor (AR) gene. For the PGK BstXI polymorphism assay, DNA samples are predigested with a methylation-sensitive endonuclease (Vogelstein et al 1987;Uehara et al 2000), while for the AR (CAG)n polymorphism assay, samples are first treated with a methylationsensitive endonuclease (Sangha et al 1999) or sodium bisulfite (Kubota et al 1999).…”

Section: Introductionmentioning

confidence: 99%

X chromosome inactivation patterns in 45,X/46,XX mosaics

et al. 2001

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To investigate X chromosome inactivation (XCI) patterns in 45,X/46,XX mosaics, genomic DNA was extracted from peripheral blood samples of 15 female subjects who showed different proportions of 45,X cell clones. XCI patterns were analyzed using two assays. The first assay was the BstXI restriction endonuclease detection of an Xlinked phosphoglycerate kinase (PGK) gene polymorphism following digestion of the DNA with methylation-sensitive HpaII, or with methylation-insensitive AfaI as a control. The second assay was the detection of a CAG triplet repeat polymorphism in the X-linked androgen receptor (AR) gene after sodium bisulfite treatment. Of the 15 subjects, 11 were informative due to heterozygosity for at least one of the polymorphisms (6 were heterozygous for the PGK polymorphism and 9 were heterozygous for the AR polymorphism). Four of the 11 informative subjects (36%) showed extremely skewed XCI for at least one of the polymorphisms, which was a much higher incidence than previously reported for normal females. Moreover, 3 of these 4 women had proportions of 45,X cell clones greater than 20%. Although our results may be due to several possible cytogenetic or molecular mechanisms, the most likely explanation is that cases of 45,X/46,XX that contain relatively high levels of 45,X cell clones probably arose due to structural aberrations of the X chromosome undetectable by conventional karyotyping.

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“…Several methods have been utilized to evaluate XCI patterns in X-linked genes with known nucleotide polymorphisms, such as intron 1 of the phosphoglycerate kinase gene which includes a BstXI site polymorphism, and exon 1 of the human androgen receptor gene (HUMARA) which includes a CAG triplet repeat [(CAG)n] polymorphism (Vogelstein et al 1987;Lanasa et al 1999aLanasa et al , 1999bSangha et al 1999;Uehara et al 2000). To assess differential methylation, samples are first treated with a methylation-sensitive endonuclease or sodium bisulfite, and then PCR-amplified.…”

Section: Introductionmentioning

confidence: 99%

CpG dinucleotide methylation patterns in the human androgen receptor gene and X-chromosome inactivation in peripheral blood leukocytes of phenotypically normal women

et al. 2003

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To evaluate methylation patterns in CpG dinucleotides (CpGs) of the human androgen receptor gene (HUMARA) and X-chromosome inactivation (XCI) status in phenotypically normal women in a general population, bisulfite genomic sequencing and methylation-specific PCR of genomic DNA extracted from peripheral blood samples of 124 phenotypically normal women were examined. CpGs methylation patterns were based on bisulfite genomic sequencing of the region containing nine CpGs in the HUMARA exon 1. The results of methylation status in CpGs from 43 independent colonies of 14 women revealed that not all CpGs were methylated even in highly methylated HU-MARA alleles, and that the methylation status in CpGs varied between clones, by the position of CpGs methylation and in each subject. Evaluation of XCI was based on the method of an HUMARA (CAG)n polymorphism assay after bisulfite modification of DNA samples. The HUMARA allele size ratios of the women (82 heterozygotes) varied over a wide range and the distribution patterns of the ratios approached a 'normal distribution'. Since excessive skewing of XCI was observed in 11-12% of women, female carriers of an X-linked hereditary disease manifest its clinical symptoms or signs possibly in maximum 5-6%.

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Extremely Skewed X-Chromosome Inactivation Is Increased in Women with Recurrent Spontaneous Abortion

Cited by 77 publications

References 28 publications

Evidence from autoimmune thyroiditis of skewed X-chromosome inactivation in female predisposition to autoimmunity

Evidence from autoimmune thyroiditis of skewed X-chromosome inactivation in female predisposition to autoimmunity

X chromosome inactivation patterns in 45,X/46,XX mosaics

CpG dinucleotide methylation patterns in the human androgen receptor gene and X-chromosome inactivation in peripheral blood leukocytes of phenotypically normal women

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