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1.
Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. 总被引:62,自引:12,他引:62
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R C Allen H Y Zoghbi A B Moseley H M Rosenblatt J W Belmont 《American journal of human genetics》1992,51(6):1229-1239
The human androgen-receptor gene (HUMARA; GenBank) contains a highly polymorphic trinucleotide repeat in the first exon. We have found that the methylation of HpaII and HhaI sites less than 100 bp away from this polymorphic short tandem repeat (STR) correlates with X inactivation. The close proximity of the restriction-enzyme sites to the STR allows the development of a PCR assay that distinguishes between the maternal and paternal alleles and identifies their methylation status. The accuracy of this assay was tested on (a) DNA from hamster/human hybrid cell lines containing either an active or inactive human X chromosome; (b) DNA from normal males and females; and (c) DNA from females showing nonrandom patterns of X inactivation. Data obtained using this assay correlated substantially with those obtained using the PGK, HPRT, and M27 beta probes, which detect X inactivation patterns by Southern blot analysis. In order to demonstrate one application of this assay, we examined X inactivation patterns in the B lymphocytes of potential and obligate carriers of X-linked agammaglobulinemia. 相似文献
2.
Amos-Landgraf JM Cottle A Plenge RM Friez M Schwartz CE Longshore J Willard HF 《American journal of human genetics》2006,79(3):493-499
X-chromosome inactivation is widely believed to be random in early female development and to result in a mosaic distribution of cells, approximately half with the paternally derived X chromosome inactive and half with the maternally derived X chromosome inactive. Significant departures from such a random pattern are hallmarks of a variety of clinical states, including being carriers for severe X-linked diseases or X-chromosome cytogenetic abnormalities. To evaluate the significance of skewed patterns of X inactivation, we examined patterns of X inactivation in a population of >1,000 phenotypically unaffected females. The data demonstrate that only a very small proportion of unaffected females show significantly skewed inactivation, especially during the neonatal period. By comparison with this data set, the degree of skewed inactivation in a given individual can now be quantified and evaluated for its potential clinical significance. 相似文献
3.
The large number of redundant sequences available in nucleotide databases provides a resource for the identification of polymorphisms. Expressed polymorphisms in X-linked genes can be used to determine the inactivation status of the genes, and polymorphisms in genes that are subject to inactivation can then be used as tools to examine X-chromosome inactivation status in heterozygous females. In this study, we have identified six new X-linked single-nucleotide polymorphisms and determined the inactivation status of these genes by examination of expression patterns in female cells previously demonstrated to have skewed inactivation, as well as by analysis of somatic cell hybrids retaining the inactive human X chromosome. Expression was seen from both alleles in females heterozygous for the RPS4X gene, confirming the previously reported expression from the inactive X chromosome. Expression of only a single allele was seen in females heterozygous for polymorphisms in the BGN, TM4SF2, ATP6S1, VBP1, and PDHA1 genes, suggesting that these genes are subject to X-chromosome inactivation. 相似文献
4.
Luigi D. Notarangelo Ornella Parolini Fulvio Porta Franco Locatelli Arnalda Lanfranchi Massimo Marconi Luigi Nespoli Alberto Albertini Ian W. Craig Alberto G. Ugazio 《Human genetics》1991,88(2):237-241
Summary We report on a thrombocytopenic female belonging to a pedigree with the Wiskott-Aldrich syndrome (WAS). Restriction fragment length polymorphism (RFLP) analysis with probe M27, closely linked to the WAS gene, demonstrated that she is a carrier of WAS. Both small-sized and normal-sized platelets were present, suggesting that, unlike the vast majority of WAS carriers, she does not manifest nonrandom X-chromosome inactivation in the thrombopoietic cell lineage. Study of X-chromosome inactivation by means of RFLP and methylation analysis demonstrated that the pattern of X-chromosome inactivation was nonrandom in T lymphocytes, but random in granulocytes. While this is the first complete report on the occurrence of thrombocytopenia in a carrier female of WAS as the result of atypical lyonization, it also suggests that expression of the WAS gene occurs at (or extends up to) a later stage than the multipotent stem cell along the hematopoietic differentiation pathway. 相似文献
5.
G. de Saint Basile L. D. Notarangelo C. Bonaiti-Pellié M. Doussau O. Prolini I. W. Craig A. Ugazio C. Griscelli A. Fischer 《Human genetics》1992,89(2):223-228
Summary Whole-blood cells of obligate carriers of the X-linked Wiskott-Aldrich syndrome (WAS) exhibit nonrandom inactivation of the X-chromosomes. However, because of the limited polymorphism of the probes available, the X-methylation pattern can only be determined in a restricted proportion of females. We thus analysed a large set of normal females and members of WAS families, using the recently described marker M27, which detects the hyperpolymorphic locus DXS255. The probe was used to detect differences in methylation between the active and inactive X-chromosome, and the findings were compared with the pattern obtained using the well-documented probes from the 5 end of the PGK and HPRT genes. All the normal females were found to use either X-chromosome randomly, and there was complete correlation between the three probes in the populations studied. Segregation analysis performed with M27 and other related markers in the WAS families was fully in accordance with the X-inactivation data. The use of M27, for both X-inactivation and segregation analysis of WAS kindreds, provides a basis for genetic counselling in the majority of families, including those with no surviving males. 相似文献
6.
Luigi D. Notarangelo Ornella Parolini Alberto Albertini Marzia Duse Evelina Mazzolari Alessandro Plebani Giovanna Camerino Alberto G. Ugazio 《Human genetics》1991,88(2):130-134
Summary The pattern of X-chromosome inactivation was analyzed, by means of two different DNA probes (pSPT-PGK and M27), in several cell lineages derived from females belonging to a pedigree with X-linked immunodeficiency with hyper-IgM (HIGM1). Non-random X-chromosome inactivation was demonstrated in T cells, B cells, and neutrophils, but not in fibroblasts, of obligate carriers, suggesting that different hematopoietic cell lineages are primarily involved in HIGM1. Preferential inactivation of the paternally derived X-chromosome was demonstrated by analysis of segregation of the alleles defined by the pSPT-PGK and M27 probes. The possibility that the HIGM1 mutation may confer a proliferative and/or differential advantage to hematopoietic precursors carrying the mutated allele on the active X-chromosome is discussed. 相似文献
7.
A. K. Naumova R. M. Plenge L. M. Bird M. Leppert K. Morgan H. F. Willard C. Sapienza 《American journal of human genetics》1996,58(6):1111-1119
One of the two X chromosomes in each somatic cell of normal human females becomes inactivated very early in embryonic development. Although the inactivation of an X chromosome in any particular somatic cell of the embryonic lineage is thought to be a stochastic and epigenetic event, a strong genetic influence on this process has been described in the mouse. We have attempted to uncover evidence for genetic control of X-chromosome inactivation in the human by examining X chromosome-inactivation patterns in 255 females from 36 three-generation pedigrees, to determine whether this quantitative character exhibits evidence of heritability. We have found one family in which all seven daughters of one male and the mother of this male have highly skewed patterns of X-chromosome inactivation, suggesting strongly that this quantitative character is controlled by one or more X-linked genes in some families. 相似文献
8.
Female mammals have two X chromosomes and males have a single X and a smaller, male-determining Y chromosome. The dosage of X-linked gene products is equalized between the sexes by the genetic inactivation of one X chromosome in females. The characteristics of the mechanism of X-chromosome inactivation differ in eutherian and metatherian mammals, and it has been suggested that the metatherian system represents a more primitive stage. The present study of monotreme sex chromosomes and X-chromosome inactivation suggests that the prototherian mammals may represent an even more primitive stage. There is extensive G-band homology between the monotreme X and Y chromosomes, and differences in the patterns of replication of the two X chromosomes in females suggest that X inactivation is tissue specific and confined to the unpaired segment of the X. On the basis of these results, we propose a model for the differentiation of mammalian sex chromosomes and the evolution of the mechanism of X-chromosome inactivation. This model involves a gradual reduction of the Y chromosome and an accompanying gradual recruitment of (newly unpaired) X-linked loci under the control of a single inactivation center. 相似文献
9.
A. K. Naumova L. Olien L. M. Bird C. Slamka M. Fonseca A. E. Verner M. Wang M. Leppert K. Morgan C. Sapienza 《Genesis (New York, N.Y. : 2000)》1995,17(3):198-205
We have begun a search for heritable variation in X-chromosome inactivation pattern in normal females to determine whether there is a genetic effect on the imprinting of X-chromosome inactivation in humans. We have performed a quantitative analysis of X-chromosome inactivation in lymphocytes from mothers in normal, three-generation families. Eight mothers and 12 grandmothers exhibited evidence of highly skewed patterns of X-chromosome inactivation. We observed that the male offspring of females with skewed X-inactivation patterns were three times more likely to inherit alleles at loci that were located on the inactive X chromosome (Xi) than the active X chromosome (Xa). The region of the X chromosome for which this phenomenon was observed extends from XP11 to -Xq22. We have also examined X-chromosome inactivation patterns in 21 unaffected mothers of male bilateral sporadic retinoblastoma patients. Six of these mothers had skewed patterns of X-chromosome inactivation. In contrast to the tendency for male offspring of skewed mothers from nondisease families to inherit alleles from the inactive X chromosome, five of the six affected males inherited the androgen receptor alleles from the active X chromosome of their mother. © 1995 Wiley-Liss, Inc. 相似文献
10.
Skewed X-chromosome inactivation in female carriers of dyskeratosis congenita. 总被引:2,自引:1,他引:1
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K Devriendt G Matthijs E Legius E Schollen D Blockmans C van Geet H Degreef J J Cassiman J P Fryns 《American journal of human genetics》1997,60(3):581-587
In this study, we report on a family with X-linked dyskeratosis congenita (DC). Linkage analysis with markers in the factor VIII gene at Xq28 yielded a LOD score of 2 at a recombination of 0. Clinical manifestations of DC, such as skin lesions following the Blaschko lines, were present in two obligate carrier females. Highly skewed X inactivation was observed in white blood cells, cultured skin fibroblasts, and buccal mucosa from female carriers of DC in this family. This suggests a critical role for the DC gene in bone marrow-cell and fibroblast-cell proliferation. 相似文献
11.
In a large family with X-linked retinitis pigmentosa 2 (XLRP2), we reexamined 7 obligate carrier females and 6 daughters of obligate carriers, whose linkage relationships suggested that they carried the XLRP2 gene. The phenotype varied from totally normal eyes through mild retinal changes to complete loss of vision. The X-inactivation analysis was carried out with the highly informative probe M27 on DNA from blood lymphocytes. This probe detects a locus DXS 255 that is differentially methylated on the active and inactive X chromosomes. In 5 blind heterozygotes (aged 43 to 68 years), we found that the X chromosome carrying the RP2 gene was methylated and active in nearly all their cells. The opposite X inactivation pattern was found in a carrier female (aged 45 years) who gave normal findings on eye examination. Carriers with less skewed X inactivation had a less severe clinical outcome. However, we found little or no correlation between their phenotypes and the methylation status of their X chromosomes. Our results suggest that it may be possible to develop a predictive test that could identify cases with severe outcome and perhaps cases with normal outcome. 相似文献
12.
X-chromosome inactivation is an epigenetic process whereby one X chromosome is silenced in mammalian female cells. Since it
was first proposed by Lyon in 1961, mouse models have been valuable tools to uncover the molecular mechanisms underlying X
inactivation. However, there are also inherent differences between mouse and human X inactivation, ranging from sequence content
of the X inactivation center to the phenotypic outcomes of X-chromosome abnormalities. X-linked gene dosage in males, females,
and individuals with X aneuploidies and X/autosome translocations has demonstrated that many human genes escape X inactivation,
implicating cis-regulatory elements in the spread of silencing. We discuss the potential nature of these elements and also review the elements
in the X inactivation center involved in the early events in X-chromosome inactivation. 相似文献
13.
Mammalian X-chromosome inactivation achieves dosage compensation between the sexes by the silencing of one X chromosome in females. In Eutheria, X inactivation is initiated by the large noncoding RNA Xist; however, it is unknown how this RNA results in silencing of the chromosome or why, at least in humans, many genes escape silencing in somatic cells. We have sequenced the coast mole Xist gene and compared the Xist RNA sequence among seven eutherians to provide insight into the structure of the RNA and origins of the gene. Using DNA methylation of promoter sequences to assess whether genes are silenced in females we report the inactivation status of seven X-linked genes in humans and mice as well as two additional eutherians, the mole and the cow, providing evidence that escape from inactivation is common among Eutheria. 相似文献
14.
15.
A stain upon the silence: genes escaping X inactivation 总被引:13,自引:0,他引:13
16.
Yamada M Ariga T Kawamura N Yamaguchi K Ohtsu M Nelson DL Kondoh T Kobayashi I Okano M Kobayashi K Sakiyama Y 《Journal of immunology (Baltimore, Md. : 1950)》2000,165(2):1119-1122
The Wiskott-Aldrich syndrome (WAS) is caused by defects in the WAS protein (WASP) gene on the X chromosome. Previous study disclosed that flow cytometric analysis of intracellular WASP expression (FCM-WASP analysis) in lymphocytes was useful for the diagnosis of WAS patients. Lymphocytes from all WAS patients showed WASPdim instead of WASPbright. Here we report that FCM-WASP analysis in monocytes could be a useful tool for the WAS carrier diagnosis. Monocytes from all nine WAS carriers showed varied population of WASPdim together with WASPbright. None of control individuals possessed the WASPdim population. In contrast, lymphocytes from all the carriers except two lacked the WASPdim population. The difference of the WASPdim population in monocytes and lymphocytes observed in WAS carriers suggests that WASP plays a more critical role in the development of lymphocytes than in that of monocytes. The present studies suggest that a skewed X-chromosomal inactivation pattern observed in WAS carrier peripheral blood cells is not fixed at the hemopoietic stem cell level but progresses after the lineage commitment. 相似文献
17.
Application of carrier testing to genetic counseling for X-linked agammaglobulinemia. 总被引:6,自引:4,他引:2
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R. C. Allen R. G. Nachtman H. M. Rosenblatt J. W. Belmont 《American journal of human genetics》1994,54(1):25-35
Bruton X-linked agammaglobulinemia (XLA) is a phenotypically recessive genetic disorder of B lymphocyte development. Female carriers of XLA, although asymptomatic, have a characteristic B cell lineage-specific skewing of the pattern of X inactivation. Skewing apparently results from defective growth and maturation of B cell precursors bearing a mutant active X chromosome. In this study, carrier status was tested in 58 women from 22 families referred with a history of agammaglobulinemia. Primary carrier analysis to examine patterns of X inactivation in CD19+ peripheral blood cells (B lymphocytes) was conducted using quantitative PCR at the androgen-receptor locus. Obligate carriers of XLA demonstrated > 95% skewing of X inactivation in peripheral blood CD19+ cells but not in CD19- cells. Carrier status for mothers of isolated affected males could be assessed in 10 of 11 families: 7 women showed skewing, and 3 did not. Five carriers were found in six families in which there were no living affected males. Among all those tested, one individual's carrier status was considered to be indeterminate and five women were noninformative for the carrier test. Results obtained by the carrier test were congruent with linkage analysis (where applicable) using the RFLPs DXS178 and DXS94 and two newly developed polymorphic microsatellite markers, DXS178CA and DXS101AAT. Refinements in techniques for primary carrier testing and genetic mapping of XLA now make possible an ordered approach to diagnosis, prenatal diagnosis, and genetic counseling. 相似文献
18.
19.
Skewed X-chromosome inactivation is a common feature of X-linked mental retardation disorders 总被引:7,自引:2,他引:5
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Plenge RM Stevenson RA Lubs HA Schwartz CE Willard HF 《American journal of human genetics》2002,71(1):168-173
Some deleterious X-linked mutations may result in a growth disadvantage for those cells in which the mutation, when on the active X chromosome, affects cell proliferation or viability. To explore the relationship between skewed X-chromosome inactivation and X-linked mental retardation (XLMR) disorders, we used the androgen receptor X-inactivation assay to determine X-inactivation patterns in 155 female subjects from 24 families segregating 20 distinct XLMR disorders. Among XLMR carriers, ~50% demonstrate markedly skewed X inactivation (i.e., patterns 80:20), compared with only ~10% of female control subjects (P<.001). Thus, skewed X inactivation is a relatively common feature of XLMR disorders. Of the 20 distinct XLMR disorders, 4 demonstrate a strong association with skewed X inactivation, since all carriers of these mutations demonstrate X-inactivation patterns 80:20. The XLMR mutations are present on the preferentially inactive X chromosome in all 20 informative female subjects from these families, indicating that skewing is due to selection against those cells in which the XLMR mutation is on the active X chromosome. 相似文献
20.
Wieland I Jakubiczka S Muschke P Cohen M Thiele H Gerlach KL Adams RH Wieacker P 《American journal of human genetics》2004,74(6):1209-1215
Craniofrontonasal syndrome (CFNS) is an X-linked craniofacial disorder with an unusual manifestation pattern, in which affected females show multiple skeletal malformations, whereas the genetic defect causes no or only mild abnormalities in male carriers. Recently, we have mapped a gene for CFNS in the pericentromeric region of the X chromosome that contains the EFNB1 gene, which encodes the ephrin-B1 ligand for Eph receptors. Since Efnb1 mutant mice display a spectrum of malformations and an unusual inheritance reminiscent of CFNS, we analyzed the EFNB1 gene in three families with CFNS. In one family, a deletion of exons 2-5 was identified in an obligate carrier male, his mildly affected brother, and in the affected females. In the two other families, missense mutations in EFNB1 were detected that lead to amino acid exchanges P54L and T111I. Both mutations are located in multimerization and receptor-interaction motifs found within the ephrin-B1 extracellular domain. In all cases, mutations were found consistently in obligate male carriers, clinically affected males, and affected heterozygous females. We conclude that mutations in EFNB1 cause CFNS. 相似文献