Mutations in the X-linked RSK2 gene (RPS6KA3) in patients with Coffin-Lowry syndrome

RSK2 is a growth factor-regulated serine-threonine protein kinase, acting i n the Ras-Mitogen-Activated Protein Kinase (MAPK) signaling pathway. Mutati ons in the RSK2 gene (RPS6KA3) on chromosome Xp22.2, have been found to cau se Coffin-Lowry syndrome (CLS), an X-linked disorder characterized by psych omotor retardation, characteristic facial and digital abnormalities, and pr ogressive skeletal deformations. By screening of 250 patients with clinical features suggestive of Coffin-Lowry syndrome, 71 distinct disease-associat ed RSK2 mutations have been identified in 86 unrelated families. Thirty-eig ht percent of mutations are missense mutations, 20% are nonsense mutations, 18% are splicing errors, and 21% are short deletion or insertion events. A bout 57% of mutations result in premature translation termination, and the vast majority are predicted to cause loss of function of the mutant allele. These changes are distributed throughout the RSK2 gene and show no obvious clustering or phenotypic association. However, some missense mutations are associated with milder phenotypes. In one family, one such mutation was as sociated solely with mild mental retardation. It is noteworthy that nine mu tations were found in female probands, with no affected male relatives, asc ertained through learning disability and mild but suggestive facial and dig ital dysmorphisms, Hum Mutat 17:103-116, 2001. (C) 2001 Wiley Liss, Inc.