Genetics
Coffin–Lowry syndrome is an X-linked disorder resulting from loss-of-function mutations in the RPS6KA3 gene, which encodes RSK2 (ribosomal S6 kinase 2). Multiple mutations have been identified in RPS6KA3 that can give rise to the disorder, including missense mutations, nonsense mutations, insertions and deletions. Individuals with CLS rarely have affected parents, suggesting that most incidents arise from de novo mutations in the germline. The lack of an inheritance pattern may be due to the fact that affected individuals are unlikely to parent children. In 20–30% of cases, however, there is a family history of disease. In these cases, the disorder is typically inherited from the maternal parent. Because RPS6KA3 is located on the X chromosome, males (who possess only one copy of the X chromosome) display more severe symptoms than females. Affected females usually possess one mutated copy of the RPS6KA3 gene and one wild type copy. Random inactivation of one copy of the X chromosome in females mitigates the impact of possessing a mutant allele. Occasionally females are born with two mutated alleles. In these cases the symptoms are as severe as in males with the disease. Cell physiology
Mutations in the RPS6KA3 gene can result in expression of an RSK2 protein (ribosomal S6 kinase 2) with reduced or absent kinase function. RSK2 is a downstream component of the MAPK (mitogen-activated protein kinase) cascade that is itself a kinase. RSK2 phosphorylates cellular proteins (including histone H3, and CREB), which regulate eukaryotic gene expression.
References
Sources
This article incorporates public domain text from The U.S. National Library of Medicine and the National Institute of Neurological Disorders and Stroke. External links

GeneReviews/UW/NIH entry on Coffin–Lowry syndrome
Coffin-Lowry syndrome: MedlinePlus Genetics