Skeletal Genetics: From Gene Identification to Murine Models of Disease

Changes in the human skeleton can result from DNA variants that are transmitted from parent to child via the normal meiotic processes. Genetic diseases can be inherited in rare disorders through Mendelian (single-gene) fashion via defined modes of inheritance, or through DNA changes that are much more common in the human population, and can consist of variants in multiple genes. Variants contributing to Mendelian traits usually produce large effects on gene function, with a single variant often being solely responsible for the observed bone phenotype. In contrast, in common diseases containing a heritable component, each genetic variant typically has a small effect, with the sum of these effects producing the observed phenotype. Once a gene or variant is found that links to a Mendelian disorder or to a structural or functional bone phenotype, these variants can be studied in vivo through the use of transgenic mouse models. The techniques and theory underlying isolating genetic changes that relate to diseases of bone, as well as the use of animal models for understanding bone function and targeted therapeutics, will be discussed in this chapter.