The mouse as a model of fundamental concepts related to Turner syndrome

Abstract

Although XO mice do not show many of the overt phenotypic features of Turner syndrome (TS; 45,X or XO), mice and humans share different classes of genes on the X chromosome that are more or less likely to cause TS phenotypes. Based on the evolutionary history of the sex chromosomes, and the pattern of dosage balancing among sex chromosomal and autosomal genes in functional gene networks, it is possible to prioritize types of X genes for study as potential causes of features of TS. For example, X‐Y gene pairs are among the most interesting because of the convergent effects of X and Y genes that both are likely to prevent the effects of TS in XX and XY individuals. Many of the high‐priority genes are shared by mouse and human X chromosomes, but are easier to study in genetically tractable mouse models. Several mouse models, used primarily for the study of sex differences in physiology and disease, also produce XO mice that can be investigated to understand the effects of X monosomy. Using these models will lead to the identification of specific X genes that make a difference when present in one or two copies. These studies will help to achieve a better appreciation of the contribution of these specific X genes to the syndromic features of TS.

The transcriptomic landscape of monosomy X (45,X) during early human fetal and placental development

“…Of note, like many lncRNAs, this gene is present in humans but not in the mouse. We hypothesize that, if OVCH1-AS1 is biologically relevant, this feature could contribute to marked differences in phenotype between monosomy X in humans and the murine model of a single X chromosome 54 . Some of the biggest questions to address are how monosomy X is such a common cause of pregnancy loss and also whether there are any specific features in those pregnancies that survive to term?…”

The contribution of Xp22.31 gene dosage to Turner and Klinefelter syndromes and sex-biased phenotypes

“…The fact that X-monosomic (39,XO) mice recapitulate several TS phenotypes (Arnold, 2019;Hinton et al, 2015;Lynn and Davies, 2007) provides further evidence that dosage of X-linked genes (some of which escape X-inactivation across species) rather than the alternative genetic mechanisms described above largely link TS genotype with phenotype. However, the relationship between genotype and phenotype in TS is complex, does not directly map from one to the other, and is dependent upon transcriptional and epigenetic factors affecting gene expression across the genome (Viuff et al, 2019).…”

The Hypothesis of the Prolonged Cell Cycle in Turner Syndrome

“…Therefore, several authors argue that XO mice cannot be used as a model to study the TS phenotype [ 24 ]. However, the XO mice are a useful model of TS because it is the only genetically tractable mammalian species in which viable female individuals with one or two X chromosomes can easily be produced [ 25 ]. For example, the XO mice have fewer oocytes compared to normal XX mice and exhibit premature ovarian failure [ 25 ].…”

“…However, the XO mice are a useful model of TS because it is the only genetically tractable mammalian species in which viable female individuals with one or two X chromosomes can easily be produced [ 25 ]. For example, the XO mice have fewer oocytes compared to normal XX mice and exhibit premature ovarian failure [ 25 ]. Also, evidence indicates that maternal monosomy X has deleterious effects on preimplantation embryo development [ 26 ].…”

“…The data published so far agree that the growth deficit in most newborns with TS is approximately −1,0 SDS [ 40 , 41 , 42 ] and the deviation from normal is relatively small. Similarly, XO mouse embryos develop more slowly than XX embryos until early mid-gestation, but they reach the same stage in their growth and development as their XX littermates at birth [ 25 ]. Ishikawa et al reported the mean number of somites was greater in XX mouse embryos than it was in XO mouse embryos [ 43 ].…”