Familial nonrandom inactivation linked to the X inactivation centre in heterozygotes manifesting haemophilia A

Bicocchi, M. P.; Migeon, Barbara R.; Pasino, M; Lanza, Tiziana; Bottini, F.; Boeri, E; Molinari, Angelo Claudio; Corsolini, Fabio; Morerio, Cristina; Acquila, Maura

doi:10.1038/sj.ejhg.5201386

Cited by 40 publications

(37 citation statements)

References 24 publications

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“…We observed segregation between the disease and marker alleles with the DNA markers residing on the distal short arm and pericentromeric regions of the X chromosome in this family. Although examples of skewed X-inactivation segregating with a trait have been reported previously, 18,26 this is the first example in AITDs to the best of our knowledge. In a recently published study on a threegeneration kindred, extreme skewing of X inactivation was documented in three female subjects who have hemophilia A.…”

Section: Discussionmentioning

confidence: 61%

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: Discussionmentioning

confidence: 61%

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

et al. 2006

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“…In two such families, a promoter mutation in the XIST gene did indeed lead to the preferential inactivation of the X chromosome carrying the mutation (Plenge et al 1997). In other families, haplotype analysis demonstrated co-segregation of a totally skewed pattern of X inactivation and a region at Xq28 (Pegoraro et al1997), one at Xq25-26 and one at Xq13 (Naumova et al 1996;Bicocchi et al 2005). In our family, no linkage was found in Xq13.2 where the XIST locus resides, and the sequencing of the minimal promoter of the XIST gene did not show any nucleotide variation.…”

Section: Discussionmentioning

confidence: 99%

A locus for familial skewed X chromosome inactivation maps to chromosome Xq25 in a family with a female manifesting Lowe syndrome

et al. 2006

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In mammals, X-linked gene products can be dosage compensated between males and females by inactivation of one of the two X chromosomes in the developing female embryos. X inactivation choice is usually random in embryo mammals, but several mechanisms can influence the choice determining skewed X inactivation. As a consequence, females heterozygous for X-linked recessive disease can manifest the full phenotype. Herein, we report a family with extremely skewed X inactivation that produced the full phenotype of Lowe syndrome, a recessive X-linked disease, in a female. The X chromosome inactivation studies detected an extremely skewed inactivation pattern with a ratio of 100:0 in the propositus as well as in five out of seven unaffected female relatives in four generations. The OCRL1 ''de novo'' mutation resides in the active paternally inherited X chromosome. X chromosome haplotype analysis suggests the presence of a locus for the familial skewed X inactivation in chromosome Xq25 most likely controlling X chromosome choice in X inactivation or cell proliferation. The description of this case adds Lowe syndrome to the list of X-linked disorders which may manifest the full phenotype in females because of the skewed X inactivation.

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“…On occasion, heterozygous females with HA have been described, and in some cases, this has been attributed to unfavourably skewed X-chromosome inactivation (XCI). 1,2 XCI is a process in mammals in which one X in every XX female somatic cell is transcriptionally silenced through CpG hypermethylation and chromatin remodelling. 3 Expression of the X-inactive-specific transcript (XIST) is required for silencing.…”

Section: Introductionmentioning

confidence: 99%

Heritable skewed X-chromosome inactivation leads to haemophilia A expression in heterozygous females

et al. 2007

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Factor VIII gene, F8, mutations cause haemophilia A (HA), an X-linked recessive disorder. Expression in heterozygous females has been ascribed to skewed X-chromosome inactivation (XCI). To investigate the cause of HA in three heterozygous females within an Atlantic Canadian kindred, the proband (severely affected girl, FVIII activity: 2%) and 17 relatives across three generations were studied. F8 genotype, FVIII activity, XCI ratio (XCIR) (paternal active X: maternal active X), karyotype, submegabase resolution tiling set array competitive genome hybridization (competitive genomic hybridization (SMRT)), and microsatellite analyses were utilized. A positive linear relationship between FVIII activity and percentageactivated normal X-chromosome was found in HA heterozygous females (R 2 ¼ 0.87). All affected, but no unaffected females, had an XCIR skewed toward activation of the mutant X-chromosome (proband 92:8, SD 2). Unexpectedly, high numbers of females have dramatically skewed XCIRs (480:20 or o20:80) (Po0.05). The distribution of XCIR frequencies within this family was significantly different than predicted by normal population data or models of random XCI (Po0.025), with more females having higher degrees of skewing. Known causes of skewing, such as chromosomal abnormalities, selection against deleterious alleles, and X-inactive-specific transcript mutations, are not consistent with our results. This study shows that FVIII activity in HA heterozygous females can be directly related to XCI skewing, and that low FVIII activity in females in this family is due to unfavourable XCI skewing. Further, the findings suggest that these XCI ratios are genetically influenced, consistent with a novel heritable human X controlling element (XCE) functioning similarly to the mouse Xce.

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Familial nonrandom inactivation linked to the X inactivation centre in heterozygotes manifesting haemophilia A

Cited by 40 publications

References 24 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

A locus for familial skewed X chromosome inactivation maps to chromosome Xq25 in a family with a female manifesting Lowe syndrome

Heritable skewed X-chromosome inactivation leads to haemophilia A expression in heterozygous females

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