Mutation analysis of the RSK2 gene in Coffin-Lowry patients: Extensive allelic heterogeneity and a high rate of de novo mutations

Coffin-Lowry syndrome (CLS) is an X-linked disorder characterized by severe psychomotor retardation, facial and digital dysmorphisms, and progressive skeletal deformations. By using a positional cloning approach, we have rece ntly shown that mutations in the gene ceding for the RSK2 serine-threonine protein kinase are responsible for this syndrome. To facilitate mutational analysis, we have now determined the genomic structure of the human RSK2 ge ne. The open reading frame of the RSK2. coding region is split into 22 exon s. Primers were designed for PCR amplification of single exons from genomic DNA and subsequent single-strand conformation polymorphism analysis. We sc reened 37 patients with clinical features suggestive of CLS. Twenty-five nu cleotide changes predicted to be disease-causing mutations were identified, including eight splice-site alterations, seven nonsense mutations, five fr ameshift mutations, and five missense mutations. Twenty three of them were novel mutations. Coupled with previously reported mutations, these findings bring the total of different RSK2 mutations to 34. These are distributed t hroughout the RSK2 gene, with no clustering, and all but two, which have be en found in two independent patients, are unique. A very high (68%) rate of de novo mutations was observed. It is noteworthy also that three mutations were found in female probands, with no affected male relatives, ascertaine d through learning disability and mild but suggestive facial and digital dy smorphisms. No obvious correlation was observed between the position or typ e of the RSK2 mutations and the severity or particular clinical features of CLS.