Highly Skewed X-Chromosome Inactivation Is Associated with Idiopathic Recurrent Spontaneous Abortion

Lanasa, Mark C.; Hogge, W. Allen; Kubik, Carolyn J.; Blancato, Jan; Hoffman, Eric P.

doi:10.1086/302441

Cited by 70 publications

(71 citation statements)

References 95 publications

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“…It is possible that different tissues in the body may have different X-inactivation patterns, for example, the brain may have a more random pattern of X-inactivation compared with blood. Previous studies in our laboratory have shown excellent concordance in X-inactivation patterns of 45 women between two types of tissues, peripheral blood cells (mesoderm) and oral mucosal cells (endoderm), 39 suggesting that tissue-specific differences in X-inactivation patterns may be rare. A limited study of X-inactivation patterns in brain tissue have shown random X-inactivation patterns for all patients.…”

Section: The Patients Were Then Divided Into Five Mutation Groups: Mbmentioning

confidence: 72%

“…In these women, the X-linked mutant locus leading to skewed X-inactivation must be on the same chromosome (in cis) with the mutant MeCP2 gene, leading to preferential inactivation of the X chromosome with the MeCP2 mutation. We have recently shown in other studies that many females showing highly skewed X-inactivation are carriers of X-linked recessive lethal disorders, which result in death or a growth disadvantage of cells having the abnormal X active 39,40 (Lanasa et al, in press). Similarly, we have found patterns of skewed X-inactivation in clinically manifesting carriers of X-linked recessive traits such as Duchenne dystrophy.…”

Section: The Patients Were Then Divided Into Five Mutation Groups: Mbmentioning

confidence: 99%

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MeCP2 mutations in children with and without the phenotype of Rett syndrome

Hoffbuhr¹,

Devaney²,

LaFleur³

et al. 2001

Neurology

227

232

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Article abstract-Background: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the X-linked methyl CpG binding protein 2 (MeCP2) gene. Methods: One hundred sixteen patients with classical and atypical RTT were studied for mutations of the MeCP2 gene by using DHPLC and direct sequencing. Results: Causative mutations in the MeCP2 gene were identified in 63% of patients, representing a total of 30 different mutations. Mutations were identified in 72% of patients with classical RTT and one third of atypical cases studied (8 of 25). The authors found 17 novel mutations, including a complex gene rearrangement found in one individual involving two deletions and a duplication. The duplication was identical to a region within the 3Ј untranslated region (UTR), and represents the first report of involvement of the 3Ј UTR in RTT. The authors also report the identification of MeCP2 mutations in two males; a Klinefelter's male with classic RTT (T158M) and a hemizygous male infant with a Xq27-28 inversion and a novel 32 bp frameshift deletion [1154(del32)]. Studies examining the relationship between mutation type, X-inactivation status, and severity of clinical presentation found significant differences in clinical presentation between different types of mutations. Mutations in the amino-terminus were significantly correlated with a more severe clinical presentation compared with mutations closer to the carboxyl-terminus of MeCP2. Skewed X-inactivation patterns were found in two asymptomatic carriers of MeCP2 mutations and six girls diagnosed with either atypical or classical RTT. Conclusion: This patient series confirms the high frequency of MeCP2 gene mutations causative of RTT in females and provides data concerning the molecular basis for clinical variability (mutation type and position and X-inactivation patterns).

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Section: The Patients Were Then Divided Into Five Mutation Groups: Mbmentioning

confidence: 72%

Section: The Patients Were Then Divided Into Five Mutation Groups: Mbmentioning

confidence: 99%

MeCP2 mutations in children with and without the phenotype of Rett syndrome

Hoffbuhr¹,

Devaney²,

LaFleur³

et al. 2001

Neurology

227

232

View full text Add to dashboard Cite

show abstract

“…Preferential XCI is an infrequent event in humans, which can be associated with conditions such as extensive X chromosome structural rearrangements, X-linked lethal traits and reduction of the number of embryonic precursor cells in the inner mass at the time of XCI commitment. 4,5 In extra-embryonic tissues of marsupials and mice, the X P is always inactivated. 3 In humans, conflicting data have been reported; of four recent studies, using the methylation assay of androgen receptor (AR), one reported X P preferential inactivation, 6 and three showed both random and preferential XCI.…”

Section: Introductionmentioning

confidence: 99%

Biparental expression of ESX1L gene in placentas from normal and intrauterine growth-restricted pregnancies

et al. 2003

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Equivalent levels of X-linked gene products between males and females are reached by means of X chromosome inactivation (XCI). In the human and murine embryonic tissues, both the paternally and maternally derived X chromosomes (X P and X M ) may be inactivated. In murine extra-embryonic tissues, X P is imprinted and always silenced; humans, unlike mice, can inactivate the X M in extra-embryonic lineages without an adverse outcome. This difference is probably due to the presence of imprinted placental genes on the murine X chromosome, but not on the human homologue, essential for placental development and function. An example is the paternally imprinted Esx1 gene; mice with a null maternally derived Esx1 allele show intrauterine growth restriction (IUGR) because of placental insufficiency. We investigated the imprinting status of the human orthologous Esx1 gene (ESX1L) in placental samples of four normal full-term and 13 IUGR female fetuses, in which we determined the XCI pattern. Our findings demonstrated that IUGR as well as normal placentas display XCI heterogeneity, thus indicating that the IUGR phenotype is not correlated with a preferential pattern of XCI in placentas. Moreover, ESX1L is equally expressed in IUGR and normal placentas, and shows the same methylation pattern in the presence of both random and skewed XCI. These findings provide evidence that ESX1L is not imprinted in human third-trimester placentas and there is no parent-of-origin effect of chromosome X associated with placental insufficiency.

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“…[18], 80% [19], and 90% have been employed [20]. In the current study, skewing of the X chromosome was defined if the percentage activity of a single allele was ≥ 80% in heterozygous samples [19].…”

Section: Hormone Assaysmentioning

confidence: 99%

Contributions of CAG repeat length in the androgen receptor gene and androgen profiles to premature pubarche in Korean girls

Kang¹,

Lee

Kim

et al. 2017

Endocr J

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Abstract. The CAG repeat length of the androgen receptor (AR) gene, which exhibits an inverse relationship to AR sensitivity, might influence the development of the pubarche along with hyperandrogenemia. There are ethnic differences in the AR CAG repeat length, however, no Asian studies on premature pubarche (PP) have been reported, including Korea. Our objectives were to examine the hormone levels and AR CAG repeat length, and to assess their contributions to PP in Korean girls. Subjects with PP (n=16) and normal pubarche (NP, n=16), and normal controls (NC, n=16) were enrolled. The levels of dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEAS), 17-hydroxyprogesterone (17-OHP), and free testosterone (FT) were checked. The methylation-weighted (MW) average CAG repeat lengths were analyzed. The median ages at pubarche were 7.4 and 8.9 years in the PP and NP groups, respectively, and the levels of 17-OHP, DHEAS, and FT were similar in both groups. The PP group exhibited a higher DHEAS:DHEA ratio than the NP group (P=0.014). The medians of the MW average CAG repeat length of the AR gene were 22.4 for all subjects and did not differ among the PP (22.3), NP (22.4), and NC (22.2) groups. The AR CAG repeat lengths in the PP and NP groups did not correlate with DHEAS or FT levels. These results suggest that the AR CAG repeat length was not involved in the development of PP in Korean girls. However, excessive adrenal androgen levels, particularly those caused by increased sulfotransferase activity, might be important in the pathogenesis of PP.

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Highly Skewed X-Chromosome Inactivation Is Associated with Idiopathic Recurrent Spontaneous Abortion

Cited by 70 publications

References 95 publications

MeCP2 mutations in children with and without the phenotype of Rett syndrome

MeCP2 mutations in children with and without the phenotype of Rett syndrome

Biparental expression of ESX1L gene in placentas from normal and intrauterine growth-restricted pregnancies

Contributions of CAG repeat length in the androgen receptor gene and androgen profiles to premature pubarche in Korean girls

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