Disease relevance of X Chromosome Inactivation

• This study was undertaken to determine the relative impact of three molecular characteristics of the FMR1 mutation--number of CGG repeats, methylation status, and X inactivation ratio--on the cognitive involvement of female carriers of fragile X syndrome [1].
• Myotubular myopathy in a girl with a deletion at Xq27-q28 and unbalanced X inactivation assigns the MTM1 gene to a 600-kb region [2].
• Bilateral retinoblastoma in a male patient with an X; 13 translocation: evidence for silencing of the RB1 gene by the spreading of X inactivation [3].
• 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 [4].
• Hemorrhagic diathesis in multiple obligate carriers in these families is not readily explained by the Lyon hypothesis, and suggests that these families may be exmaples of an unusual allelic form of hemophilia A or that they may be transmitting several independent genes affecting VIII AHF levels [5].

Psychiatry related information on X Chromosome Inactivation

• An 806delG deletion causing a V288X stop in the transcription-repression domain was identified in a woman with motor-coordination problems, mild learning disability, and skewed X inactivation; in her sister and daughter, who were affected with classic RTT; and in her hemizygous son, who died from congenital encephalopathy [6].
• We report on deletion mapping and X inactivation analysis of a gene for X linked non-specific mental retardation (MRX) at Xp21.3-Xp22.11, on the basis of molecular studies in two families with Xp microdeletions involving the DAX-1 gene [7].
• Girls with Rett syndrome exhibit mosaic expression for the MeCP2 defect at the cellular level, with most patients showing random X-inactivation and approximately equal numbers of cells expressing the normal MeCP2 gene and the mutated MeCP2 gene [8].

High impact information on X Chromosome Inactivation

• Using a Cre-loxP system, we generated knockout animals lacking Ofd1 and reproduced the main features of the disease, albeit with increased severity, possibly owing to differences of X inactivation patterns between human and mouse [9].
• Moreover, we suggest that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling and propose that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X inactivation) explains the higher prevalence of the disease in males [10].
• Homozygous Tsix mutant mice reveal a sex-ratio distortion and revert to random X-inactivation [11].
• The gene Xist initiates the chromosomal silencing process of X inactivation in mammals [12].
• X inactivation of the OCNC1 channel gene reveals a role for activity-dependent competition in the olfactory system [13].

Chemical compound and disease context of X Chromosome Inactivation

• Some female carriers of a vasopressin type-2 receptor mutation may show complete manifestation of nephrogenic diabetes insipidus, probably as a result of skewed X-inactivation [14].

Biological context of X Chromosome Inactivation

• X chromosome inactivation, XIST, and pursuit of the X-inactivation center [15].
• Methylation occurs around the time of inactivation and earlier for Pgk-1, which is closer to the X-inactivation centre [16].
• This gene, ANT3, is located approximately 1,300 kilobases from the telomere, proximal to the pseudoautosomal gene CSF2RA, and escapes X-inactivation [17].
• Homologous ribosomal protein genes on the human X and Y chromosomes: escape from X inactivation and possible implications for Turner syndrome [18].
• A short region of the human X chromosome containing several genes, including that necessary for the expression of steroid sulphatase (STS), is exceptional in that it apparently escapes X-inactivation [19].

Anatomical context of X Chromosome Inactivation

• In contrast to effects in embryonic stem cells, deleting Tsix causes ectopic X inactivation in early male embryos and inactivation of both X chromosomes in female embryos, indicating that X chromosome counting cannot override Tsix imprinting [20].
• We find that heterozygotes who are more than 10 yr old have an excess of HPRT+ skin fibroblast clones (59% rather than the 50% expected as a consequence of random X inactivation) but this excess does not increase with age [21].
• A skewed pattern of X inactivation was demonstrated in DNA isolated from the patient's kidney and white blood cells: > 90% of the X chromosomes with the normal COL4A5 allele was inactivated [22].
• However, analysis of replication timing in cell lines with skewed X inactivation showed no preference for one of the two Xist alleles to replicate early in S-phase before the onset of X inactivation, indicating that asynchronous replication timing does not play a role in skewing of X inactivation [23].
• Female carriers of XLA, although asymptomatic, have a characteristic B cell lineage-specific skewing of the pattern of X inactivation [24].

Associations of X Chromosome Inactivation with chemical compounds

• Mouse PRC2 (mPRC2) has been implicated in X inactivation, as mPRC2 proteins transiently accumulate on the inactive X chromosome (Xi) at the onset of X inactivation to methylate histone H3 lysine 27 (H3-K27) [25].
• In 2 of 4 families studied, the maternal grandmothers had normal NBT tests, suggesting either nonrandom X-inactivation or new mutations [26].
• To identify differentially methylated domains (DMDs) at the X-inactivation center, we used bisulfite sequencing and methylation-sensitive restriction enzyme analyses [27].
• In addition, our observations of continued XIST expression in 5aC-treated hybrids with reactivated genes indicates that such expression is not sufficient for the maintenance of X inactivation [28].
• Telomere length was measured by an in-gel hybridization technique, X-inactivation ratios were measured by the human androgen receptor assay, and cell cycle status was determined by flow cytometric analysis of pyronin Y- and Hoechst 33342-stained CD34(+)CD90(+) and CD34(+)CD90(-) marrow cells [29].

Gene context of X Chromosome Inactivation

• Tsix, a gene antisense to Xist at the X-inactivation centre [30].
• These results highlight differences between imprinted and random X inactivation but show that Tsix regulates both [20].
• The localization of the XIST gene to the XIC region on the human X chromosome implicates XIST in some aspect of X inactivation [31].
• Xite, X-inactivation intergenic transcription elements that regulate the probability of choice [32].
• We have identified its counterpart within the human X inactivation center (XIC) [33].

Analytical, diagnostic and therapeutic context of X Chromosome 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 [34].
• Northern blot analysis of RNA from these hybrids showed that the human MIC2 gene, which is known to escape X inactivation, was transcribed in hybrids with either the active or inactive X chromosome [35].
• Genetic studies included karyotyping to detect mosaicism, genotyping of microsatellite markers to determine parental origin of the supernumerary X-chromosome, and genotyping and methylation studies to measure AR polyglutamine (AR CAGn) repeat length and X inactivation ratio [36].
• Studies of both the FMR-1 and the androgen receptor loci using PCR based X-inactivation analysis demonstrated that in all families analyzed, there is preferential inactivation of one X chromosome [37].
• By immunofluorescence and chromatin immunoprecipitation experiments we show that histone H3 lysine 27 trimethylation (H3K27m3) and H4 lysine 20 monomethylation (H4K20m1) are associated with Xist expression in undifferentiated ES cells and mark the initiation of X inactivation [38].

References