Abstract
BackgroundPentasomy X (49,XXXXX) has been associated with a severe clinical condition, presumably resulting from failure or disruption of X chromosome inactivation. Here we report that some human X chromosomes from a patient with 49,XXXXX pentasomy were functionally active following isolation in inter-specific (human-rodent) cell hybrids. A comparison with cytogenetic and molecular findings provided evidence that more than one active X chromosome was likely to be present in the cells of this patient, accounting for her abnormal phenotype.Results5-bromodeoxyuridine (BrdU)-pulsed cultures showed different patterns among late replicating X chromosomes suggesting that their replication was asynchronic and likely to result in irregular inactivation. Genotyping of the proband and her mother identified four maternal and one paternal X chromosomes in the proband. It also identified the paternal X chromosome haplotype (P), indicating that origin of this X pentasomy resulted from two maternal, meiotic non-disjunctions. Analysis of the HUMANDREC region of the androgen receptor (AR) gene in the patient's mother showed a skewed inactivation pattern, while a similar analysis in the proband showed an active paternal X chromosome and preferentially inactivated X chromosomes carrying the 173 AR allele. Analyses of 33 cell hybrid cell lines selected in medium containing hypoxanthine, aminopterin and thymidine (HAT) allowed for the identification of three maternal X haplotypes (M1, M2 and MR) and showed that X chromosomes with the M1, M2 and P haplotypes were functionally active. In 27 cell hybrids in which more than one X haplotype were detected, analysis of X inactivation patterns provided evidence of preferential inactivation.ConclusionOur findings indicated that 12% of X chromosomes with the M1 haplotype, 43.5% of X chromosomes with the M2 haplotype, and 100% of the paternal X chromosome (with the P haplotype) were likely to be functionally active in the proband's cells, a finding indicating that disruption of X inactivation was associated to her severe phenotype.
Highlights
Pentasomy X (49,XXXXX) has been associated with a severe clinical condition, presumably resulting from failure or disruption of X chromosome inactivation
The proband carried four different maternal X chromosomes; the fourth one corresponding to the maternal haplotype (MR) counterpart that was not found in the cell hybrid panel
Under the hypothesis of random X inactivation, the theoretically expected five equal classes of cells with one active X chromosome and four inactive X chromosomes were unlikely to be present in the proband because the paternal X chromosome was always active, accounting for a 5-fold increase with respect to its expected proportion (20%)
Summary
Pentasomy X (49,XXXXX) has been associated with a severe clinical condition, presumably resulting from failure or disruption of X chromosome inactivation. Analysis of histone H4 acetylation in a group of patients with 49,XXXXX, 49,XXXXY, 48,XXXY and 47,XXX karyotypes showed alterations in deacetylation of histone H4 once the inactive state was established [37] These alterations might have affected the outcome in determining the number and the choice of which X chromosomes were deacetylated, probably due to the presence of more than one X chromosome undergoing inactivation. These results suggested that supernumerary X chromosomes might be associated to abnormal phenotypes due to excess of X active regions or to increased asynchronism of X chromosome replication, mainly in patients with four or five X chromosomes
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