Dosage Compensation in Females with X-Linked Metabolic Disorders

Abstract

Through the use of new genomic and metabolomic technologies, our comprehension of the molecular and biochemical etiologies of genetic disorders is rapidly expanding, and so are insights into their varying phenotypes. Dosage compensation (lyonization) is an epigenetic mechanism that balances the expression of genes on heteromorphic sex chromosomes. Many studies in the literature have suggested a profound influence of this phenomenon on the manifestation of X-linked disorders in females. In this review, we summarize the clinical and genetic findings in female heterozygotic carriers of a pathogenic variant in one of ten selected X-linked genes whose defects result in metabolic disorders.

Keywords: X chromosome inactivation; X-linked inheritance; XCI; inborn errors of metabolism; metabolic disorders.

Figure 1

Model of X chromosome inactivation (XCI) in female human early development [14,15]. Female zygote inherits active maternal and paternal X chromosomes (Xm and Xp, respectively). Biallelic XIST expression starts from the four-cell stage concomitant with embryo genome activation and is upregulated in the blastocyst, in which progressive random XCI begins. The embryo at this stage consists of cells with either both X chromosomes active (white) or one X chromosome partially inactivated (red or blue). It is believed that complete XCI stabilizes between early implantation and the end of the first month of the pregnancy with different kinetics depending on cell lineage [16]. The XCI pattern established at the stage of gastrula and its three germ layers is stably maintained and clonally propagated through cell divisions. Nevertheless, the exact timing of complete XCI in humans remains elusive, as investigations past the blastocyst stage remain beyond current capabilities.

Figure 2

Tissues in which proteins are affected in the disorders described in this review are most abundantly produced and their embryonic origin. Tissue protein expression is based on data obtained from GeneCards^®: The Human Gene Database; https://www.genecards.org/ (accessed on 27 January 2021) available as data integrated from literature manual curation, proteomics, and transcriptomics screens, and automatic text mining. Origin from germ layers is indicated for each tissue. Figure created using the human body figure designed by brgfx/Freepik (www.freepik.com; accessed on 27 January 2021).