Intronic L1 insertion and F268S, novel mutations in RPS6KA3 (RSK2) causing Coffin–Lowry syndrome

Two novel mutations of the ribosomal S6 kinase 2 gene (also known as RSK2 ) have been identified in two unrelated patients with Coffin–Lowry syndrome. The first mutation consists of a de novo insertion of a 5′‐truncated LINE‐1 element at position −8 of intron 3, which leads to a skipping of exon 4, leading to a shift of the reading frame and a premature stop codon. The L1 fragment (2800 bp) showed a rearrangement with a small deletion, a partial inversion of the ORF 2, flanked by short direct repeats which duplicate the acceptor splice site. However, cDNA analysis of the patient shows that both sites are apparently not functional. The second family showed the nucleotide change 803T>C in exon 10, resulting in the F268S mutation. This mutation was detected in two monozygotic twin patients and in their mother, who was mildly affected. The patients fulfill the clinical criteria of the syndrome, and therefore the mutation provides further support for the importance of phenylalanine at position 268, which is highly conserved in the protein kinase domain of many serine–threonine protein kinases.