Abstract
Turner's syndrome (caused by monosomy of chromosome X) is one of the most common chromosomal abnormalities in females. Although 3% of all pregnancies start with XO embryos, 99% of these pregnancies terminate spontaneously during the first trimester. The common genetic explanation for the early lethality of monosomy X embryos, as well as the phenotype of surviving individuals is haploinsufficiency of pseudoautosomal genes on the X chromosome. Another possible mechanism is null expression of imprinted genes on the X chromosome due to the loss of the expressed allele. In contrast to humans, XO mice are viable, and fertile. Thus, neither cells from patients nor mouse models can be used in order to study the cause of early lethality in XO embryos. Human embryonic stem cells (HESCs) can differentiate in culture into cells from the three embryonic germ layers as well as into extraembryonic cells. These cells have been shown to have great value in modeling human developmental genetic disorders. In order to study the reasons for the early lethality of 45,XO embryos we have isolated HESCs that have spontaneously lost one of their sex chromosomes. To examine the possibility that imprinted genes on the X chromosome play a role in the phenotype of XO embryos, we have identified genes that were no longer expressed in the mutant cells. None of these genes showed a monoallelic expression in XX cells, implying that imprinting is not playing a major role in the phenotype of XO embryos. To suggest an explanation for the embryonic lethality caused by monosomy X, we have differentiated the XO HESCs in vitro an in vivo. DNA microarray analysis of the differentiated cells enabled us to compare the expression of tissue specific genes in XO and XX cells. The tissue that showed the most significant differences between the clones was the placenta. Many placental genes are expressed at much higher levels in XX cells in compare to XO cells. Thus, we suggest that abnormal placental differentiation as a result of haploinsufficiency of X-linked pseudoautosomal genes causes the early lethality in XO human embryos.
Highlights
Turner’s Syndrome results from X chromosome monosomy
In order to ensure that each clone was originated from a single cell, the Human embryonic stem cells (HESCs) were transfected with a plasmid carrying the neo-resistance gene
In order to detect 45,XO clones that originate from 46,XX cells we examined several heterozygous polymorphic microsattalites on the X chromosome
Summary
Turner’s Syndrome results from X chromosome monosomy. This syndrome described in 1938 [1], is the most common sex chromosome abnormality in females [2]. Several molecular mechanisms have been suggested to explain the phenotypes observed in Turner’s syndrome [5]. Of these mechanisms the most plausible explanation is haploinsufficiency of genes that are normally expressed from the two X chromosomes. In this case, the affected phenotypes are the result of the dosage of the specific gene. The affected phenotypes are the result of the dosage of the specific gene Another logical explanation is the presence of imprinted genes on the X chromosome, which are expressed in a mono-allelic fashion. One major argument against the imprinting hypothesis is that it predicts that the phenotype will depend upon the parental origin of the single X chromosome and there is very little evidence for this [5]
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