PATHOGENESIS OF COFFIN-LOWRY SYNDROME

Coffin-Lowry syndrome (CLS, MIM#303600) is an X-linked semidominant disorder. In males disorder is characterized by severe mental retardation with distinctive phenotype of face and hands, and with abnormalities in osteoarticular system. In females the intensity of symptoms is variable. Coffin-Lowry syndrome is caused in the majority of cases by mutations in the RSK2 gene (RPS6KA3) located in Xp22.2 region. The RSK2 gene encodes for RSK2 protein that belongs to a family of serine-threonine kinases acting in the MAPK/ERK signalling pathway. RSK2 protein consists of 740 amino acids and is composed of two kinase domains. RSK proteins are involved in various processes responsible for cellular proliferation and differentiation, cellular stress response, and apoptosis. Up to now about 130 different mutations in the RSK2 gene in 160 patients with Coffin-Lowry syndrome have been identified. Two-thirds of the identified mutations cause the premature introduction of a termination codon, leading to the absence of the functional serine-threonine kinase. Eighty percent of all identified mutations appeared de novo. The detectability of mutations in the RSK2 gene is about 40%. Mental retardation characteristic for Coffin-Lowry syndrome is caused by the absence of the functional RSK2 protein in the MAPK/ERK signalling pathway, involved in creating new synaptic junctions and long-term memory modeling. Abnormalities in the phosphorylation of the transcription factor ATF4 are responsible for creating defects in skeletal system.