RSK2 enzymatic assay as a second level diagnostic tool in Coffin-Lowry syndrome

Background: Coffin-Lowry syndrome is a semi-dominant condition characterized by severe psychomotor retardation with facial, hand and skeletal malformations resulting from mutations in RSK2 gene, encoding for a serine/threonine kinase. More than 100 different mutations have been identified to date; however, about 50% of clinically diagnosed patients apparently do not have mutations. In order to exclude that these patients have RSK2 mutations missed by standard mutation detection techniques, a rapid and sensitive assay allowing evaluation of RSK2 activity was needed. Methods: RSK2 capacity to phosphorylate a synthetic CREB-peptide in basal and PMA-stimulated conditions was evaluated in lymphoblasts from 3 patients with RSK2 mutations and normal controls. Results: Patients RSK2 activity is normal in nonstimulated conditions but fails to grow following stimulation. The evaluation of the stimulated/ non-stimulated activity ratio demonstrated a statistically significant impairment in patients. Conclusions: We have set up an assay which allows the identification of even partial alterations of RSK2 activity and seems to give good results also in females with a balanced X-chromosome inactivation and thus with a presumably normal enzymatic activity in about 50% of cells. Moreover, our data seem to confirm previous reports of a potential direct correlation between the level of RSK2 activity and the severity of cognitive impairment