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Sex Chromosomes and Testosterone: A Novel Mouse Model Sheds Light on the Etiology of Klinefelter Syndrome

Abstract

Klinefelter syndrome (KS) occurs when boys are born with a second X chromosome so their cells are XXY instead of XY. Men with KS have low testosterone, infertility, obesity and metabolic dysfunction, and some conditions that typically affect women such as osteoporosis, lupus, and breast cancer. Notably, they exhibit cognitive differences such as speech delay in early childhood and difficulty with executive functions as adults. Historically, KS symptoms were thought to be primarily due to low testosterone levels, yet testosterone treatment does not cure KS. Therefore, we hypothesize that direct genetic effects of the second X chromosome play an essential role. Previously, it was impossible to separate the influence of genes vs. hormones, but our lab has established the novel Sex Chromosome Trisomy (SCT) mouse model, which can be used to distinguish the two factors. The SCT model produces mice with XY and XXY chromosomes that are either male or female. XXY males have low testosterone so differences between the male groups may be due either genetic or hormonal differences. However, both female groups have low testosterone, so differences in females provide strong evidence for direct genetic effects.

We find that XXY mice have an obesity phenotype like that seen in human KS, and that sex chromosomes influence this trait, though the genetic effect may be facilitated by the presence of hormones. The mice also show an osteoporosis phenotype like humans that we find to be influenced by hormones only. Finally, a preliminary study in another mouse model of KS, the XY* model, show XXY* mice may have executive functions deficit like those seen in humans. Next steps should test the executive functioning in the SCT model, and to also measure pup vocalizations as a model of speech delay. Further research should expand the use of the model to gene expression studies to identify which genes are responsible for direct genetic effects in SCT mice. Ideally the SCT model will be increasingly characterized and lead to a better understanding of the genetic factors at play in KS, potentially leading to better treatment options for KS patients.

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