MUTATIONS IN THE KINASE RSK-2 ASSOCIATED WITH COFFIN-LOWRY SYNDROME

THE Coffin-Lowry syndrome (CLS), an X-linked disorder, is characterize d by severe psychomotor retardation, facial and digital dysmorphisms, and progressive skeletal deformations(1). Genetic linkage analysis map ped the CLS locus to an interval of 2-3 megabases at Xp22.2. The gene coding for Rsk-2, a member of the growth-factor-regulated protein kina ses, maps within the candidate interval, and was tested as a candidate gene for CLS. Initial screening for mutations in the gene for Rsk-2 i n 76 unrelated CLS patients revealed one intragenic deletion, a nonsen se, two splice site, and two missense mutations. The two missenses aff ect sites critical for the function of Rsk-2. The mutated Rsk-2 protei ns were found to be inactive in a S6 kinase assay. These findings prov ide direct evidence that abnormalities in the MAPK/RSK signalling path way cause Coffin-Lowry syndrome.