Systemic knockout of EIF2AK3 downstream target ATF4−/− or its regulatory kinase, RPS6KA3−/−, results in severe osteopenia and phenotypes similar to WRS and CLS.52,139 With phenotypes of ATF4−/−, RPS6KA3−/−, and EIF2AK3−/− mice suggesting a functional role of EIF2AK3/ATF4 signaling in bone development, it is important to note that secondary effects on bone due to gene inactivation in non-skeletal tissues cannot be excluded. This evidence concerns the gene EIF2AK3 and Wolcott-Rallison syndrome.