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Akihiro Morikawa - One of the best experts on this subject based on the ideXlab platform.
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Detection of Skewed X-Inactivation in Two Female Carriers of Vasopressin Type 2 Receptor Gene Mutation
The Journal of clinical endocrinology and metabolism, 1997Co-Authors: Yoko Nomura, Kazumichi Onigata, Tomohisa Nagashima, Shigenori Yutani, Hiroshi Mochizuki, Kanji Nagashima, Akihiro MorikawaAbstract:Most cases of congenital nephrogenic diabetes insipidus (NDI) are inherited in an X-linked manner, which is due to the mutations of the vasopressin type 2 receptor (V2R) gene. However, recent reports have presented female NDI patients with heterozygote V2R gene mutations. The mechanism of inheritance was thought to be Skewed X-Inactivation. We present a family with congenital NDI. Three male members were diagnosed with NDI, and examination of their V2R gene revealed a G inserted at nucleotide 804 of the open reading frame. Three female individuals display different degrees of symptoms of NDI, and all of them possess both the normal and abnormal genes. The X-Inactivation patterns of the female members were investigated via the detection of methylated trinucleotide repeat in the human androgen receptor gene. The grandmother showed extremely Skewed methylation of one X chromosome, and the mother revealed moderately Skewed methylation. The daughter of the grandmother's sister, who has no symptoms of NDI, showed random methylation. The highly Skewed X-Inactivation pattern of the grandmother suggests that her NDI phenotype is caused by dominant methylation of the normal allele of V2R gene.
Karen Helene Ørstavik - One of the best experts on this subject based on the ideXlab platform.
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Skewed X inactivation and survival: a 13-year follow-up study of elderly twins and singletons
European journal of human genetics : EJHG, 2011Co-Authors: Jonas Mengel-from, Karen Helene Ørstavik, Mikael Thinggaard, Lene Christiansen, James W. Vaupel, Kaare ChristensenAbstract:In mammalian females, one of the two X chromosomes is inactivated in early embryonic life. Females are therefore mosaics for two cell populations, one with the maternal and one with the paternal X as the active X chromosome. A Skewed X inactivation is a marked deviation from a 50:50 ratio. In populations of women past 55–60 years of age, an increased degree of skewing (DS) is found. Here the association between age-related skewing and mortality is analyzed in a 13-year follow-up study of 500 women from three cohorts (73–100 years of age at intake). Women with low DS had significantly higher mortality than the majority of women who had a more Skewed DS (hazard ratio: 1.30; 95% CI: 1.04–1.64). The association between X inactivation and mortality was replicated in dizygotic twin pairs for which the co-twin with the lowest DS also had a statistically significant tendency to die first in the twin pairs with the highest intra-pair differences in DS (proportion: 0.71; 95% CI: 0.52–0.86). Both results suggest that lower DS is associated with higher mortality. We therefore propose that age-related skewing may be partly due to a population selection with lower mortality among those with higher DS.
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Increased skewing of X chromosome inactivation in Rett syndrome patients and their mothers
European journal of human genetics : EJHG, 2006Co-Authors: Gun Peggy Knudsen, Tracey C. S. Neilson, June Pedersen, Alison Kerr, Marianne Schwartz, Hultén, Mark E.s. Bailey, Karen Helene ØrstavikAbstract:Rett syndrome is a largely sporadic, X-linked neurological disorder with a characteristic phenotype, but which exhibits substantial phenotypic variability. This variability has been partly attributed to an effect of X chromosome inactivation (XCI). There have been conflicting reports regarding incidence of Skewed X inactivation in Rett syndrome. In rare familial cases of Rett syndrome, favourably Skewed X inactivation has been found in phenotypically normal carrier mothers. We have investigated the X inactivation pattern in DNA from blood and buccal cells of sporadic Rett patients (n=96) and their mothers (n=84). The mean degree of skewing in blood was higher in patients (70.7%) than controls (64.9%). Unexpectedly, the mothers of these patients also had a higher mean degree of skewing in blood (70.8%) than controls. In accordance with these findings, the frequency of Skewed (XCI ≥80%) X inactivation in blood was also higher in both patients (25%) and mothers (30%) than in controls (11%). To test whether the Rett patients with Skewed X inactivation were daughters of Skewed mothers, 49 mother–daughter pairs were analysed. Of 14 patients with Skewed X inactivation, only three had a mother with Skewed X inactivation. Among patients, mildly affected cases were shown to be more Skewed than more severely affected cases, and there was a trend towards preferential inactivation of the paternally inherited X chromosome in Skewed cases. These findings, particularly the greater degree of X inactivation skewing in Rett syndrome patients, are of potential significance in the analysis of genotype–phenotype correlations in Rett syndrome.
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Skewed X inactivation in healthy individuals and in different diseases.
Acta paediatrica (Oslo Norway : 1992). Supplement, 2006Co-Authors: Karen Helene ØrstavikAbstract:UNLABELLED In female mammalian cells, one of the two X chromosomes is inactivated in early embryonic life. Females are mosaics for two cell populations, one with the maternal and one with the paternal X as the active chromosome. Skewed X inactivation is arbitrarily defined, often as a pattern where 80% or more of the cells show a preferential inactivation of one X chromosome. Inactivation is presumed to be permanent for all descendants of a cell; however, after about 55 years of age, the frequency of Skewed X inactivation in peripheral blood cells increases, probably through selection. Unfavourable skewing of X inactivation, where the X chromosome carrying a mutant allele is the predominantly active X, has been found in affected female carriers of several X-linked disorders; however, for many X-linked disorders, a consistent relationship between the pattern of X inactivation and clinical phenotype has been difficult to demonstrate. One reason for this may be that peripheral blood cells are not a representative or relevant tissue in many disorders. In some severe X-linked disorders, post-inactivation selection takes place against the X chromosome carrying the mutant allele, leading to a completely Skewed X-Inactivation pattern. Skewed X inactivation has also been reported in young females with breast cancer, and may indicate an effect of X-linked genes on the development of this condition. CONCLUSION The process of X inactivation and the resultant degree of skewing is clearly important for the expression of genetic diseases. It is also important to consider, however, that under normal conditions the frequency of Skewed X inactivation increases with age in peripheral blood cells. Analysis of the expression of a large proportion of the genes on the X chromosome has revealed that X-chromosome inactivation is more heterogeneous than previously thought.
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Skewed X inactivation in healthy individuals and in different diseases. Commentary
Acta Paediatrica, 2006Co-Authors: Karen Helene Ørstavik, Amparo Chabas, Rudolf HappleAbstract:In female mammalian cells, one of the two X chromosomes is inactivated in early embryonic life. Females are mosaics for two cell populations, one with the maternal and one with the paternal X as the active chromosome. Skewed X inactivation is arbitrarily defined, often as a pattern where 80% or more of the cells show a preferential inactivation of one X chromosome. Inactivation is presumed to be permanent for all descendants of a cell; however, after about 55 years of age, the frequency of Skewed X inactivation in peripheral blood cells increases, probably through selection. Unfavourable skewing of X inactivation, where the X chromosome carrying a mutant allele is the predominantly active X, has been found in affected female carriers of several X-linked disorders; however, for many X-linked disorders, a consistent relationship between the pattern of X inactivation and clinical phenotype has been difficult to demonstrate. One reason for this may be that peripheral blood cells are not a representative or relevant tissue in many disorders. In some severe X-linked disorders, post-inactivation selection takes place against the X chromosome carrying the mutant allele, leading to a completely Skewed X-Inactivation pattern. Skewed X inactivation has also been reported in young females with breast cancer, and may indicate an effect of X-linked genes on the development of this condition. Conclusion: The process of X inactivation and the resultant degree of skewing is clearly important for the expression of genetic diseases. It is also important to consider, however, that under normal conditions the frequency of Skewed X inactivation increases with age in peripheral blood cells. Analysis of the expression of a large proportion of the genes on the X chromosome has revealed that X-chromosome inactivation is more heterogeneous than previously thought.
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Myopathy with skeletal asymmetry and hemidiaphragm elevation is caused by myotubularin mutations.
Neurology, 2005Co-Authors: P. M. Grogan, Karen Helene Ørstavik, Gun Peggy Knudsen, S. M. Tanner, David Saperstein, Hannes Vogel, Richard J. Barohn, Laura Herbelin, April Mcvey, Jonathan S. KatzAbstract:The authors report two families with a myopathy phenotype affecting only women, marked by asymmetric weakness, skeletal asymmetry, and an elevated hemidiaphragm. One family had a mutation in a stop codon in exon 9 of the myotubularin gene, and the other had a splice site mutation in exon 13. Both families had manifesting and nonmanifesting carriers. Skewed X-Inactivation appeared to explain the clinical manifestations in only one of the two families.
Mary D. Stephenson - One of the best experts on this subject based on the ideXlab platform.
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Pregnancy outcome in recurrent miscarriage patients with Skewed X chromosome inactivation
Obstetrics and gynecology, 2003Co-Authors: Amy E. Sullivan, Tracey Lewis, Mary D. Stephenson, Randall R. Odem, James R. Schreiber, Carole Ober, D. Ware BranchAbstract:Abstract Objective To analyze X inactivation in women with recurrent miscarriage to estimate whether Skewed X inactivation is associated with recurrent miscarriage and whether it predicts next pregnancy outcomes. Methods A multicenter study was performed. A power calculation determined that 101 patients were needed to detect a difference in Skewed X inactivation between patients and controls. Patients were entered into a prospective trial of mononuclear-cell immunotherapy and subsequently tested for Skewed X inactivation. Age-matched controls had one live birth and no prior miscarriages. Results from our X inactivation assay were compared with those from an independent genetics laboratory. Results Greater than 75% skewing was seen in 22.6% of patients and 26.5% controls (P = .52). Greater than 90% skewing was seen in 6.6% of patients and 3.9% of controls (P = .77). There were 19.8% of primary aborters and 32% of secondary aborters with greater than 75% Skewed X inactivation (P = .38). There were 4.9% of primary aborters and 12.0% of secondary aborters with greater than 90% Skewed X inactivation (P = .27) Neither greater than 75% nor greater than 90% Skewed X inactivation impacted next pregnancy outcomes (odds ratios = 0.87 [95% confidence interval (CI) 0.34, 2.3] and 1.4 [95% CI 0.27, 7.5], respectively). Results of the exchange of samples with an independent laboratory were highly correlated (α = 0.987, P Conclusion Skewed X chromosome inactivation is not associated with recurrent miscarriage. A patient’s X chromosome inactivation status does not predict next pregnancy outcome. Our assay correlates with another experienced laboratory.
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Skewed X Inactivation and Recurrent Spontaneous Abortion
Seminars in reproductive medicine, 2001Co-Authors: Wendy P. Robinson, Cl Beever, Carolyn J. Brown, Mary D. StephensonAbstract:Recent studies show that women experiencing recurrent spontaneous abortion exhibit nonrandom X-chromosome inactivation (XCI) more often than in controls. This suggests that genetic factors may be important in explaining the losses in this subset of women. Nonetheless there are a number of possible explanations for this finding and the underlying causes may be heterogeneous. One hypothesis commonly cited is that a mutation on the X chromosome results in both preferential inactivation of the mutated X as well as lethality of male embryos inheriting this mutated X. However, this hypothesis does not explain the increase in chromosome abnormalities observed in the karyotyped losses from women with recurrent pregnancy loss and Skewed XCI. This finding leads us to suggest that the mechanism involved may be associated with a reduction in number of ovarian follicles, either due to X mutations affecting oocyte atresia or a restriction in precursor pool size during development.
Matthew F. Reeves - One of the best experts on this subject based on the ideXlab platform.
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Recurrent spontaneous abortion and Skewed X-Inactivation: is there an association?
American journal of obstetrics and gynecology, 2007Co-Authors: W. Allen Hogge, Tracy L Prosen, Mark C. Lanasa, Heather A. Huber, Matthew F. ReevesAbstract:Objective The purpose of this study was to determine whether there is an association between Skewed X-Inactivation and recurrent spontaneous abortion in a large, well-defined sample of women with recurrent loss. Study Design X-chromosome inactivation patterns were compared in 5 groups of women. Group 1 (recurrent spontaneous abortion) consisted of 357 women with 2 or more spontaneous losses. In group 2 (infertility), there were 349 subjects from infertility practices recruited at the time of a positive serum beta-human chorionic gonadotropin. Group 3 (spontaneous abortion) women (n = 81) were recruited at the time of an ultrasound diagnosis of an embryonic demise or an anembryonic gestation. Groups 4 (primiparous) and 5 (multiparous) were healthy pregnant subjects previously enrolled in another study to determine the incidence and cause of pregnancy complications, such as preeclampsia and intrauterine growth restriction. The Primiparous group included 114 women in their first pregnancy, whereas the Multiparous group consisted of 79 women with 2 or more pregnancies but without pregnancy loss. Results The rate of extreme skewing (90% or greater) in the recurrent spontaneous abortion population was 8.6%, and not statistically different from any of the other groups, except the Primiparous group (1.0%, P P > .05). When age and skewing of 90% or greater are compared, subjects with extreme skewing have a mean age of 2 years older than those without extreme skewing ( P Conclusion Skewed X-Inactivation is not associated with recurrent spontaneous abortion but is associated with increasing maternal age.
Atsuko Yoshizawa-ogasawara - One of the best experts on this subject based on the ideXlab platform.
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Correlation between Clinical Phenotypes and X-Inactivation Patterns in Six Female Carriers with Heterozygote Vasopressin Type 2 Receptor Gene Mutations
Endocrine journal, 2008Co-Authors: Mari Satoh, Sayaka Ogikubo, Atsuko Yoshizawa-ogasawaraAbstract:About 90% of patients with congenital nephrogenic diabetes insipidus (NDI) have vasopressin type 2 receptor (V2R) gene mutations that are inherited in an X-linked recessive manner. Although most female carriers are asymptomatic, some female carriers show polydipsia and polyuria. The reason why female carriers show NDI symptoms is explained by Skewed X-Inactivation. We studied X-Inactivation patterns of six female carriers with heterozygote V2R gene mutations. The X-Inactivation pattern in peripheral blood leukocytes was examined using methylation analysis of the polymorphic CAG repeat in the androgen receptor gene. Two asymptomatic female carriers showed random X-Inactivation (61.9% and 60.7%). Skewed X-Inactivation patterns (71.6%, 79.4%, and 91.2%) occurring preferentially to normal X alleles were recognized in three female carriers who showed clinical NDI symptoms. However, in one female carrier who showed clinical NDI symptoms, random X-Inactivation (55.4%) was recognized. In conclusion, the clinical NDI phenotypes may correlate with the X-Inactivation patterns in female carriers with heterozygote V2R gene mutations. However, in some female carriers, we cannot predict the clinical phenotypes by the evaluation of the X-Inactivation patterns in peripheral blood leukocytes, because X-Inactivation ratios within an individual are sometimes different between tissues.