Chromosome imbalance as a driver of sex disparity in disease

Abstract

It has long been recognized that men and women exhibit different risks for diverse disorders ranging from metabolic to autoimmune diseases. However, the underlying causes of these disparities remain obscure. Analysis of patients with chromosomal abnormalities, including Turner syndrome (45X) and Klinefelter syndrome (47XXY), has highlighted the importance of X-linked gene dosage as a contributing factor for disease susceptibility. Escape from X-inactivation and X-linked imprinting can result in transcriptional differences between normal men and women as well as in patients with sex chromosome abnormalities. Animal models support a role for X-linked gene dosage in disease with O-linked N-acetylglucosamine transferase (OGT) emerging as a prime candidate for a pleiotropic effector. OGT encodes a highly regulated nutrient-sensing epigenetic modifier with established links to immunity, metabolism and development.

Keywords: Klinefelter syndrome; O-GlcNAcylation; Turner syndrome; dosage compensation; imprinting.

Figure 1

Expression of an X-linked imprinted gene. X-linked imprinting would result in differential expression between males and females. (A) A paternally expressed X-linked imprinted gene would only be expressed in about half of female cells and not expressed in male cells. (B) A maternally expressed X-linked imprinted gene would be expressed in all cells of a male and only half the cells of a female. The inactive X chromosome is represented in red, the active X chromosome is represented in green and transcription is represented by an arrow.

Figure 2

Mating schemes to derive monosomic X mice. (A) 39X^PO mice are derived by mating an In(X)1h mutant female (In(X)1h/X) with a wild type male. The In(X)1h sex chromosome contains a large inversion (represented by an X in the chromosome). If crossing over during meiosis occurs within the inversion, gametes without an X chromosome will be produced. (B) 39X^MO mice are derived by mating a wild type female (X/X) with a Paf mutant male (X^Paf/Y). The Paf mutation (represented by a red line) is located at the pseudoautosomal region and causes nondisjunction during spermatogenesis, producing sperm without a sex chromosome. Genotypes of mice are indicated below.

Figure 3

OGT is a good candidate connecting X-linked gene dosage to epigenetic regulation of metabolism and disease susceptibility. OGT is located on the X-chromosome, close to XIST and is subject to X-inactivation in mammalian females (silenced chromosome is depicted in red). Variation of OGT expression and the abundance of its substrate UDP-GlcNAc by glucose intake (Glc), modulate O-GlcNAc dynamism. This post-translational modification (represented by a green G) affects various processes from epigenetics to embryogenesis and immunity. O-GlcNAcylation is also involved in metabolism and cardiovascular defects, two of the major features of X-linked abnormalities.

Figure 4

X-linked gene dosage contributes to sex disparities in disease. Observations from Turner and Klinefelter syndrome patients have uncovered a role for X-linked gene dosage in contributing to sex disparities in disease risk. Differences in expression of genes that escape X-inactivition, like those within the pseudoautosomal region, epigenetic modifiers, like OGT, and X-linked imprinted genes (Imp.) could all contribute to disease susceptibility. Active chromosomes are represented in green, inactive chromosomes are represented in red, transcription is represented with an arrow and loss of repression represented by a dotted arrow.