IMEX   05356
INSTITUTO DE MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Molecular characterisation of variants on non-coding RNA genes in the X-inactivation centre from three symptomatic carriers with severe Haemophilia A (HA) AND EXTREMELY SKEWED X-CHROMOSOME INACTIVATION.
Autor/es:
MIGUEL TEZANOS PINTO; PRIMIANI L; C. PAMELA RADIC; CARLOS D. DE BRASI; DANIELA NEME; VANINA MARCHIONE; LILIANA C. ROSSETTI; MIGUEL CANDELA; MARTÍN M ABELLEYRO
Lugar:
Berlin
Reunión:
Congreso; XXVI Bienal Congress and 63rd Annual Scientific and Standardization Committee (SSC) Meeting of the International Society on Thrombosis and Haemostasis (ISTH); 2017
Institución organizadora:
Sociedad Internacional de Hemostasia y Trombosis
Resumen:
Background: Random X-chromosome inactivation (XCI) of one of the two X-chromosomes in females achieves dosage equivalency for X-linked genes with males. Non-coding RNA genes were described in X-chromosome inactivation centre (XIC, Xq13) associated with the inactivation process: XIST (X-inactive specific transcript), JPX (just proximal to XIST) and FTX (five prime to XIST). We hypothesize that exonic SNPs (single nucleotide polymorphism) may modify XIC gene expression or function impacting its allelic ability to inactivate.Aim: Study the association between SNP variants on relevant sequences XIST, JPX and FTX with extremely skewed XCI in three symptomatic carriers with severe HA.Methods: A comprehensive genetic variant screening of XIST, JPX and FTX was performed in leukocyte-extracted DNA samples from three symptomatic carriers with severe HA and extremely skewed XCI (97-100%) and 11 controls with random XCI (50-55%) by CSGE (conformation sensitive gel electrophoresis) and Sanger sequencing. Symptomatic carriers were previously F8 genotyped as heterozygous for severe HA mutations and the phenotypic expression resulted from their association in cis with the preferential X-inactive (Radic et al., JTH 2015,13:530-9).Results: Analysis of the non-coding RNA genes on XIC from the three cases showed no deleterious mutations, but 12 SNP variants of the 161 annotated in public databases: 5/80 SNPs on XIST, 4/46 on FTX and 3/35 JPX in heterozygous status (Table 1). Despite this observation, these variants were also found in controls (Table 1).Conclusions: This is the first study of XIST/FTX/JPX variants about the ability of XCI skewing performed thus far. The finding of SNPs in both groups (i.e., symptomatic carriers and controls) indicated no causal effect on XCI skewing. A suggestive absence of SNP heterocigosity in some DNA segments may indicate the involvement of large deletions that may destroy the ability to inactivate.