X-inactivation and human disease: X-linked dominant male-lethal disorders

doi:10.1016/j.gde.2006.04.012

Current Opinion in Genetics & Development

Volume 16, Issue 3, June 2006, Pages 254-259

https://doi.org/10.1016/j.gde.2006.04.012 Get rights and content

X chromosome inactivation (XCI) is the process by which the dosage imbalance of X-linked genes between XX females and XY males is functionally equalized. XCI modulates the phenotype of females carrying mutations in X-linked genes, as observed in X-linked dominant male-lethal disorders such as oral-facial-digital type I (OFDI) and microphthalmia with linear skin-defects syndromes. The remarkable degree of heterogeneity in the XCI pattern among female individuals, as revealed by the recently reported XCI profile of the human X chromosome, could account for the phenotypic variability observed in these diseases. Furthermore, the recent characterization of a murine model for OFDI shows how interspecies differences in the XCI pattern between Homo sapiens and Mus musculus result in discrepancies between the phenotypes observed in patients and mice.

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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X-inactivation and human disease: X-linked dominant male-lethal disorders

Introduction

Section snippets

X-linked dominant male-lethal disorders

Conclusions

References and recommended reading

Acknowledgements

Am J Hum Genet

Genomics

J Med Genet

J Med Genet

Genes Dev

Hum Mol Genet

X-inactivation profile reveals extensive variability in X linked gene expression in females

Nature

Skewed X inactivation in X-linked disorders

Semin Reprod Med

Studies of a family with the oral facial–digital syndrome

N Engl J Med

X-linked dominant inherited diseases with lethality in hemizygous males

Hum Genet

Oro-facio-digital syndrome 1

Oral–facial–digital syndromes, 1992

Clin Dysmorphol

Neuropathology of oral–facial–digital syndromes

Arch Pathol Lab Med

Central nervous system malformations and early end-stage renal disease in oro–facio–digital syndrome type 1: a review

Am J Med Genet

Orofaciodigital syndrome with cerebral dysgenesis

Am J Med Genet A

The oral-facial-digital syndrome: a male-lethal condition in a boy with 47/XXY chromosomes

Pediatrics

A male with type I orofaciodigital syndrome

J Med Genet

Oral facial–digital syndrome type I in a newborn male

Am J Med Genet

Characterization of Cxorf5 (71 7A), a novel human cDNA mapping to Xp22 and encoding a protein containing coiled-coil a-helical domains

Genomics

OFD1, the gene mutated in oral–facial digital syndrome type 1, is expressed in the metanephros and in human embryonic renal mesenchymal cells

J Am Soc Nephrol