Skewed X-Chromosome Inactivation Is a Common Feature of X-Linked Mental Retardation Disorders

Plenge, Robert M.; Stevenson, Roger; Lubs, Herbert A.; Schwartz, Charles E.; Willard, Huntington F.

doi:10.1086/341123

Cited by 216 publications

(180 citation statements)

References 24 publications

(31 reference statements)

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“…Since the presence of an X-linked mutation may cause the presence of skewed X-chromosome inactivation in the lymphocytes of carrier women, 16 we tested the X-inactivation profile in each woman of this family, using the AR gene polymorphic repeated sequence on DNA prepared from fresh blood samples. All the obligate carrier women exhibited a highly skewed X-inactivation pattern (Figure 1a), which is consistent with findings previously reported for families with XNP/ATR-X mutations.…”

Section: Resultsmentioning

confidence: 99%

Mutation in the 5′ alternatively spliced region of the XNP/ATR-X gene causes Chudley–Lowry syndrome

et al. 2004

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The Chudley-Lowry syndrome (ChLS, MIM 309490) is an X-linked recessive condition characterized by moderate to severe mental retardation, short stature, mild obesity, hypogonadism, and distinctive facial features characterized by depressed nasal bridge, anteverted nares, inverted-V-shaped upper lip, and macrostomia. The original Chudley -Lowry family consists of three affected males in two generations. Linkage analysis had localized the gene to a large interval, Xp21 -Xq26 and an obligate carrier was demonstrated to have highly skewed X inactivation. The combination of the clinical phenotype, consistent with that of the patients with ATR-X syndrome, the skewed X-inactivation pattern in a carrier female, as well as the mapping interval including band Xq13.3, prompted us to consider the XNP/ATR-X gene being involved in this syndrome. Using RT-PCR analysis, we screened the entire XNP/ATR-X gene and found a mutation in exon 2 (c.109C4T) giving rise to a stop codon at position 37 (p.R37X). Western blot and immunocytochemical analyses using a specific monoclonal antibody directed against XNP/ATR-X showed the protein to be present in lymphoblastoid cells from one affected male, despite the premature stop codon. To explain these discordant results, we further analyzed the 5 0 region of the XNP/ATR-X gene and found three alternative transcripts, which differ in the presence or absence of exon 2, and the length of exon 1. Our data suggest that ChLS is allelic to the ATR-X syndrome with its less severe phenotype being due to the presence of some XNP/ATR-X protein.

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Section: Resultsmentioning

confidence: 99%

Mutation in the 5′ alternatively spliced region of the XNP/ATR-X gene causes Chudley–Lowry syndrome

et al. 2004

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“…Skewing of XCI was also reported in rare cases of balanced X/autosome translocations, which perturbed the normal mechanisms of XCI (10). Furthermore, skewing has been associated with some complex traits such as recurrent abortion (11) and mental retardation (12), although the causative role of skewing in these situations has not been established. Skewing is a common feature of tumorigenic processes in which an acquired somatic mutation occurs in a single progenitor cell that subsequently undergoes clonal expansion and gives rise to progeny with the same XCI pattern (13,14).…”

Section: Introductionmentioning

confidence: 99%

No evidence that skewing of X chromosome inactivation patterns is transmitted to offspring in humans

Bolduc¹,

Chagnon²,

Provost³

et al. 2008

J. Clin. Invest.

102

122

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Skewing of X chromosome inactivation (XCI) can occur in normal females and increases in tissues with age. The mechanisms underlying skewing in normal females, however, remain controversial. To better understand the phenomenon of XCI in nondisease states, we evaluated XCI patterns in epithelial and hematopoietic cells of over 500 healthy female mother-neonate pairs. The incidence of skewing observed in mothers was twice that observed in neonates, and in both cohorts, the incidence of XCI was lower in epithelial cells than hematopoietic cells. These results suggest that XCI incidence varies by tissue type and that age-dependent mechanisms can influence skewing in both epithelial and hematopoietic cells. In both cohorts, a correlation was identified in the direction of skewing in epithelial and hematopoietic cells, suggesting common underlying skewing mechanisms across tissues. However, there was no correlation between the XCI patterns of mothers and their respective neonates, and skewed mothers gave birth to skewed neonates at the same frequency as nonskewed mothers. Taken together, our data suggest that in humans, the XCI pattern observed at birth does not reflect a single heritable genetic locus, but rather corresponds to a complex trait determined, at least in part, by selection biases occurring after XCI. IntroductionIn mammals, dosage compensation of X-linked genes in females is achieved by the transcriptional silencing of 1 of the 2 X chromosomes during early development, a process known as X chromosome inactivation (XCI) (1). Once XCI has occurred, the heterochromatin-enriched inactive X chromosome is stably transmitted to each daughter cell through subsequent mitoses. In human and mouse embryos, either of the 2 X chromosomes (paternal or maternal) can be inactivated. As a consequence, females from both species present a mosaic pattern of 2 cell lines, one expressing maternal X-linked genes and the other expressing paternal X-linked genes. The XCI ratio (or XCI pattern) corresponds to the relative proportion of each cell line. This ratio can be determined by the analysis of expression (2), transcription (3), or differential methylation (4) of polymorphic X-linked genes, such as the human androgen receptor (HUMARA) gene (5). Significant deviation from the theoretical 1:1 ratio between the 2 parental alleles is called skewing. As it was first suggested by pioneers of X-inactivation analysis, including Fialkow (6) and Vogelstein (7), in most studies, skewing and extreme skewing are arbitrarily defined as greater than or equal to 75% and greater than or equal to 90% of cells expressing the same X chromosome, respectively.Skewed patterns of XCI were initially found in female carriers of specific X-linked mutations (8, 9) where skewing resulted from

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“…X chromosome inactivation (XCI) is a random process by which the majority of genes on one of the two X chromosomes present in females are silenced by an epigenetic mechanism (Lyon, 1961). Increased XCI skewing has been observed in several human diseases with relevance to autism, such as Rett syndrome (Huppke et al, 2006;Knudsen et al, 2006) and X-linked mental retardation (MR) (Plenge et al, 2002). Increased skewing can result from multiple mechanisms including X-linked mutations and reduction in the pool of cells at the time of XCI in early embryogenesis (Brown et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

MECP2 promoter methylation and X chromosome inactivation in autism

et al. 2008

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Epigenetic mechanisms have been proposed to play a role in the etiology of autism. This hypothesis is supported by the discovery of increased MECP2 promoter methylation associated with decreased MeCP2 protein expression in autism male brain. To further understand the influence of female X chromosome inactivation (XCI) and neighboring methylation patterns on aberrant MECP2 promoter methylation in autism, multiple methylation analyses were peformed on brain and blood samples from individuals with autism. Bisulfite sequencing analyses of a region 0.6 kb upstream of MECP2 in brain DNA samples revealed an abrupt transition from a highly methylated region in both sexes to a region unmethylated in males and subject to XCI in females. Chromatin immunoprecipitation analysis demonstrated that the CCTC-binding factor (CTCF) bound to this transition region in neuronal cells, consistent with a chromatin boundary at the methylation transition. Male autism brain DNA samples displayed a slight increase in methylation in this transition region, suggesting a possible aberrant spreading of methylation into the MECP2 promoter in autism males across this boundary element. In addition, autistic female brain DNA samples showed evidence for aberrant MECP2 promoter methylation as an increase in the number of bisulfite sequenced clones with undefined XCI status for MECP2 but not androgen receptor (AR). To further investigate the specificity of MECP2 methylation alterations in autism, blood DNA samples from females and mothers of males with autism were also examined for XCI skewing at AR, but no significant increase in XCI skewing was observed compared to controls. These results suggest that the aberrant MECP2 methylation in autism brain DNA samples is due to locus-specific rather than global X chromosome methylation changes.

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Skewed X-Chromosome Inactivation Is a Common Feature of X-Linked Mental Retardation Disorders

Cited by 216 publications

References 24 publications

Mutation in the 5′ alternatively spliced region of the XNP/ATR-X gene causes Chudley–Lowry syndrome

Mutation in the 5′ alternatively spliced region of the XNP/ATR-X gene causes Chudley–Lowry syndrome

No evidence that skewing of X chromosome inactivation patterns is transmitted to offspring in humans

MECP2 promoter methylation and X chromosome inactivation in autism

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