IMEX   05356
INSTITUTO DE MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Molecular characterisation of variants on non­coding RNA genes in the X­inactivation centre from three symptomatic carriers with severe haemophilia A (HA) and extremely skewed X-chromosome inactivation.
Autor/es:
ABELLEYRO M.M.; CANDELA M.; ROSSETTI L.C.; RADIC C.P.; PRIMIANI L.; TEZANOS PINTO M; MARCHIONE V.D.; NEME D.; DE BRASI C.D.
Lugar:
Berlín
Reunión:
Congreso; 26th Biennial Congress and 63rd Annual Scientific and Standardization Committee (SSC) Meeting of the International Society on Thrombosis and Haemostasis (ISTH); 2017
Institución organizadora:
International Society on Thrombosis and Haemostasis (ISTH)
Resumen:
PB 1975 | Molecular Characterisationof Variants on Non-coding RNA Genes in the X-inactivation Centre from ThreeSymptomatic Carriers with Severe Haemophilia A (HA) and Extremely SkewedX-chromosome Inactivation.C.P. Radic1,M.M. Abelleyro1, V.D. Marchione1, L. Primiani2, M. Candela3, D. Neme2, M.Bonduel4, M. de Tezanos Pinto2,3, L.C. Rossetti1, C.D. De Brasi1,3.1Institutode Medicina Experimental (IMEX), CONICET-Academia Nacional de Medicina (ANM),Ciudad Autónoma de Buenos Aires, Argentina, 2Fundación de la Hemofilia AlfredoPavlovsky, Ciudad Autónoma de Buenos Aires, Argentina, 3Instituto deInvestigaciones Hematológicas Mariano R. Castex (IIHEMA), ANM., Ciudad Autónomade Buenos Aires, Argentina, 4Laboratorio de Hemostasia y Trombosis, Hospital dePediatría, Prof Dr. Juan P. Garrahan, Ciudad Autónoma de Buenos Aires,Argentina.Background:Random X-chromosome inactivation (XCI) of one X-chromosome in females achievesdosage equivalency for X-linked genes with males. Non-coding RNA genes weredescribed in the X-chromosome inactivation centre (XIC, Xq13) associated withthe inactivation process: XIST (X-inactive specific transcript), JPX (justproximal to XIST) and FTX (five prime to XIST). We hypothesized that SNPs(single nucleotide polymorphism) may modify XIC gene expression or functionimpacting its allelic ability to inactivate.Aims: Studythe association between SNP variants on relevant sequences of XIST, JPX and FTXwith extremely skewed XCI in three symptomatic carriers with severe HA.Methods: Anextensive genetic variant screening of XIST, JPX and FTX was performed inleukocyte-extracted DNA samples from three symptomatic carriers with severe HAand extremely skewed XCI (97-100%) and 11 controls with random XCI (50-55%) byCSGE (conformation sensitive gel electrophoresis) and Sanger sequencing.Symptomatic Carriers were previously F8 genotyped as heterozygous for severe HAmutations and the phenotypic expression resulted from their association in ciswith 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 nodeleterious mutations, but 12 SNP variants out of161 annotated in publicdatabases: 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 addressing their ability onXCI skewing performed thus far. The finding of SNPs in both groups (i.e., symptomaticcarriers and controls) indicated no causal effect on XCI skewing. A suggestiveabsence of SNP heterocigosity in some DNA segments may indicate the involvementof large deletions that may hinder the ability to inactivate the X in cis.