ATF4 and Intellectual disability: Coffin-Lowry Syndrome (CLS) is an X-lined condition characterized by severe intellectual disability, delayed development, craniofacial and skeletal abnormalities.50,51 CLS is caused by a mutation in RPS6KA3, encoding ribosomal S6 kinase A3, which is known to activate ATF4.52 In normal osteoblasts RPS6KA3 is thought to phosphorylate ATF4, inducing osteoblast specific gene expression and posttranslational regulation of type I collagen synthesis.52 Therefore, UPR dysfunction may contribute to the skeletal defects seen in CLS as theorized by lack of RPS6KA3 function.