X-inactivation and human disease: X-linked dominant male-lethal disorders
Introduction
X chromosome inactivation (XCI) is the process by which one of the two X chromosomes becomes transcriptionally inactive in each somatic cell of mammalian females. The purpose of this dosage compensation mechanism is to functionally equalize the gene dosage imbalance of X-linked genes between XX females and XY males. Interestingly, some genes (approximately 15%) escape XCI, and are expressed from both the active and the inactive X chromosomes in females [1••]. The XCI pattern of genes (i.e. monoallelic as apposed to biallelic expression) might vary in various respects: among individuals within the same species [1••] (see also the review by CM Valley and HF Willard [2], this issue); among different species, such as human and mouse (see the example of the OFD1 gene, below); or among different tissues — although this has not been formally demonstrated. The choice of which of the two X chromosomes becomes inactive is completely random in a normal situation and, once initiated, is stably propagated to all daughter cells. This process has important implications for the effects seen in diseases that are due either to mutations in X-linked genes or to numerical or structural anomalies of the X chromosome. An important consequence of XCI is that heterozygous females are a mosaic of two populations of cells that have either the wild type or the disease allele active. In principle, in heterozygous female individuals carrying mutations in X-linked genes, the ratio of the two types of cells should be approximately 50:50; however, skewing of XCI can occur, thereby altering this ratio. Skewed XCI can be due to either positive or negative cell selection mechanisms. This can modulate the expression of disease manifestations of X-linked recessive disorders in females. Different degrees of skewing can also be responsible for the variable severity of the phenotypes in women carrying X-linked dominant mutations. Familial skewing of XCI has also being described [3]. A schematic representation of the effects of cell selection that lead to skewed XCI is depicted in Figure 1.
In this review, we focus on the influence that XCI has on the phenotypic expression of X chromosome mutations in female individuals. To illustrate this, we use the example of X-linked dominant male-lethal disorders, such as oral–facial–digital type I (OFDI) and microphthalmia with linear skin-defects (MLS) syndromes, in which XCI might play a role in the variability of expression of the disease phenotypes. In addition, we discuss how differences between Homo sapiens and Mus musculus in the X-inactivation status could account for discrepancies between the phenotypes observed in the patients and those of the corresponding murine models.
Section snippets
X-linked dominant male-lethal disorders
An X-linked disorder is described as dominant if it is expressed in heterozygotes. A subgroup of X-linked dominant disorders includes those characterized by male lethality or reduced male-viability. Table 1 lists all the disorders that fit into this category, including those recognized more recently, and summarizes their main features, as well as the pattern of XCI typically observed in patients. The corresponding gene has been identified for six of these disorders. According to studies
Conclusions
Although the past four decades have witnessed major advances in the understanding of the processes underlying dosage compensation between sexes in mammals, the mechanism of XCI continues to puzzle investigators. There is clear evidence that the expression of X-linked mutations in females is regulated and highly influenced by these processes. X-linked dominant male-lethal disorders represent a paradigmatic example of such influences. The observations reviewed here emphasize the importance of
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We would like to thank the Telethon Foundation for funding our research and for continuous support. We thank Dr Manuela Morleo for helpful discussion.
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2020, Epilepsy ResearchCitation Excerpt :Potential mechanisms of pathogenicity in the absence of family history in dominant variants include denovo variants, genetic mosaicism, variable penetrance, phenotypic variability and in case of X-linked dominant disorders like CDKL5, skewed X-chromosome inactivation.( Biesecker and Spinner, 2013; Franco and Ballabio, 2006; Tarailo-Graovac et al., 2017) The gold standard would be for all novel variants, even in known genes, to undergo functional assessment in a model system, which in our case was based on understanding of in-silico prediction in the results and after confirmation of the variants on Sanger sequencing. Given the prevalence of heterozygous missense variants in our series it was particularly relevant for us to establish whether the variants were de-novo or inherited which was not possible given financial and logistic limitations.