Análisis de polimorfismos en los genes del centro de inactivación e inactivación sesgada del cromosoma X en humanos
X chromosome inactivation (XCI) is a normal process by which one of the two X chromosomes of women is inactivated to compensate the gene dosage with XY males. XCI occurs early in the development and the choice of X to be inactivated is random resulting in mosaic females with 50% of cells with the pa...
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| Formato: | Tesis de maestría acceptedVersion |
| Lenguaje: | Español |
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Facultad de Farmacia y Bioquímica
2016
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| Acceso en línea: | http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=afamaster&cl=CL1&d=HWA_1542 http://repositoriouba.sisbi.uba.ar/gsdl/collect/afamaster/index/assoc/HWA_1542.dir/1542.PDF |
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| Sumario: | X chromosome inactivation (XCI) is a normal process by which one of the two X chromosomes of women is inactivated to compensate the gene dosage with XY males. XCI occurs early in the development and the choice of X to be inactivated is random resulting in mosaic females with 50% of cells with the paternal X active and the other 50% with the maternal X active. Skewed XCI is a marked deviation of 50% and, among other causes, may be associated with mutations on the XIST gene (X-inactive specific transcript) responsible for the initiation and maintenance of XCI. On the X chromosome inactivation center (XIC), on Xq13, has been described three genes associated with non-coding RNA (RNAnc) involved in XCI process: XIST, JPX (just proximal to XIST) and FTX (five prime to XIST). The presence of SNP (single nucleotide polymorphism) variants in the XIC genes may modify their expression level, their function and may impact in the allelic balance leading to skewed XCI. A molecular exploratory study type "Case/Control" (n=22) was performed to investigate the possible association between genetic variants in XIC genes with the pattern of XCI, on 11 Cases with extreme skewed XCI (XIP> 90%) and 11 Controls with random inactivation (50%>XIP<55%). In the first group, symptomatic and non-symptomatic carriers, and non-carriers, of Hemophilia A (HA) and Duchenne Muscular Dystrophy (DMD) were included. A genetic screening of XIST, JPX and FTX was performed using screening by CSGE (conformation sensitive gel electrophoresis) and Sanger sequencing, including those regions with SNPs associated with relevant allele frequencies. The study of a total of 990 amplicons analyzed showed no deletions or new mutations, only 18 allelic variants out of the 161 SNPs annotated in databases for the three genes. Eleven of 18 showed ORs associated with XCI skewing risk (e.g., OR>2.0) although no statistically significant (p>0.05). XIST variants rs6527, rs16992443, rs16992436 y rs16992442 showed ORs ranging 3-4; FTX, rs174138, rs68124822, rs146632102 y rs187332478 with ORs of 2-6 and JPX variants, rs68178357, rs55824328 y rs67649459, ORs of 2-3. These statistical data together with the bioinformatic studies performed in silico to investigate potential modifications in exonic splicing enhancer sites (ESE) and predictors of splice sites on the informative SNPs showed no clear evidence of phenotype causality although most of them mapped to phylogenetically conserved regions. Our results, although still inconclusive, encourage us to extend the series of Cases and, even more, of controls to increase the statistical consistency of the study either to confirm or rule out the preliminary observed trends. Additionally, the absence of heterozygous SNPs in some regions of XIC genes in some Cases suggests the possible association with large deletions that may abolish their role of XCI of the affected X chromosome in cis. |
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