Novel mutations in Rsk-2, the gene for Coffin-Lowry syndrome (CLS)

Coffin-Lowry syndrome (CLS) is an X-linked disorder characterized by facial dysmorphism, digit abnormalities and severe psychomotor retardation, CLS h ad previously been mapped to Xp22.2. Recently, mutations in the ribosomal S 6 kinase (Rsk-2) gene were shown to be associated with CLS, We have tested five unrelated individuals with CLS for mutations in nine exons of Rsk-2 us ing Single Strand Conformation Polymorphism (SSCP) analysis. Two patients h ad the same missense mutation (C340T), which causes an arginine to tryptoph an change (R114W), This mutation falls just outside the N-terminal ATP-bind ing site in a highly conserved region of the protein and may lead to struct ural changes since tryptophan has an aromatic side chain whereas arginine i s a 5 carbon basic amino acid, The third patient also had a missense mutati on (G2186A) resulting in an arginine to glutamine change (R729Q), The fourt h patient had a 2 bp deletion (AG) of bases 451 and 452, This creates a fra meshift that results in a stop codon 25 amino acids downstream, thereby pro ducing a truncated protein. This deletion also falls within the highly cons erved amino-catalytic domain of the protein, The fifth patient has a nonsen se mutation (C2065T) which results in a premature stop codon, thereby produ cing a truncated protein. These mutations further confirm Rsk-2 as the gene involved in CLS and may help in understanding the structure and function o f the protein.