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

Abstract

RSK2 is a growth factor-regulated serine-threonine protein kinase, acting in the Ras-Mitogen-Activated Protein Kinase (MAPK) signaling pathway. Mutations in the RSK2 gene (RPS6KA3) on chromosome Xp22.2, have been found to cause Coffin-Lowry syndrome (CLS), an X-linked disorder characterized by psychomotor retardation, characteristic facial and digital abnormalities, and progressive skeletal deformations. By screening of 250 patients with clinical features suggestive of Coffin-Lowry syndrome, 71 distinct disease-associated RSK2 mutations have been identified in 86 unrelated families. Thirty-eight percent of mutations are missense mutations, 20% are nonsense mutations, 18% are splicing errors, and 21% are short deletion or insertion events. About 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 associated solely with mild mental retardation. It is noteworthy that nine mutations were found in female probands, with no affected male relatives, ascertained through learning disability and mild but suggestive facial and digital dysmorphisms.

Identification of novel mutations in the RSK2 gene (RPS6KA3) in patients with Coffin–Lowry syndrome

“…In the present study, no mutation was found in over 60% of patients referred for mutation screening, fitting well with our previous data (2). To further determine what proportion of these patients has a mutation in RSK2 that has not been detected, we have investigated, by western blot analysis, in vitro kinase assay, cell lines from 15 patients, in whom no mutation was previously identified by SSCP analysis.…”

“…No consistent relationship between specific mutations and the severity of the disease or the expression of particular features has so far been found (2). Although only partial clinical records have been available, the data from our present study further support this conclusion (Table 1).…”

Identification of novel mutations in the RSK2 gene (RPS6KA3) in patients with Coffin–Lowry syndrome

“…In the present study, no mutation was found in over 60% of patients referred for mutation screening, fitting well with our previous data (2). To further determine what proportion of these patients has a mutation in RSK2 that has not been detected, we have investigated, by western blot analysis, in vitro kinase assay, cell lines from 15 patients, in whom no mutation was previously identified by SSCP analysis.…”

“…No consistent relationship between specific mutations and the severity of the disease or the expression of particular features has so far been found (2). Although only partial clinical records have been available, the data from our present study further support this conclusion (Table 1).…”

Mutations in the RSK2(RPS6KA3) gene cause Coffin–Lowry syndrome and nonsyndromic X‐linked mental retardation

“…Another case reported briefly in the literature details a male who was mildly delayed and worked independently as a janitor. He also had a proximally placed missense mutation (11). The mutation in this man and the brothers reported by Manouvrier-Hanu et al were located in the proximal kinase domain of the protein, which corresponds to the location of the mutation in our cases.…”

Unusual Splice-Site Mutations in the RSK2 Gene and Suggestion of Genetic Heterogeneity in Coffin-Lowry Syndrome

“…No RSK2 mutation has been detected in 66% (165/ 250) of the patients who were investigated by SSCP analysis (Delaunoy et al 2001). Even if mutations have been missed by SSCP in 27% of these patients, as suggested by the present article, 50% of patients who have no RSK2 defect remain.…”

Identification of novel mutations in the RSK2 gene (RPS6KA3) in patients with Coffin–Lowry syndrome

“…In the present study, no mutation was found in over 60% of patients referred for mutation screening, fitting well with our previous data (2). To further determine what proportion of these patients has a mutation in RSK2 that has not been detected, we have investigated, by western blot analysis, in vitro kinase assay, cell lines from 15 patients, in whom no mutation was previously identified by SSCP analysis.…”

“…No consistent relationship between specific mutations and the severity of the disease or the expression of particular features has so far been found (2). Although only partial clinical records have been available, the data from our present study further support this conclusion (Table 1).…”

Mutations in the RSK2(RPS6KA3) gene cause Coffin–Lowry syndrome and nonsyndromic X‐linked mental retardation

“…Another case reported briefly in the literature details a male who was mildly delayed and worked independently as a janitor. He also had a proximally placed missense mutation (11). The mutation in this man and the brothers reported by Manouvrier-Hanu et al were located in the proximal kinase domain of the protein, which corresponds to the location of the mutation in our cases.…”

Unusual Splice-Site Mutations in the RSK2 Gene and Suggestion of Genetic Heterogeneity in Coffin-Lowry Syndrome

“…No RSK2 mutation has been detected in 66% (165/ 250) of the patients who were investigated by SSCP analysis (Delaunoy et al 2001). Even if mutations have been missed by SSCP in 27% of these patients, as suggested by the present article, 50% of patients who have no RSK2 defect remain.…”

Identification of novel mutations in the RSK2 gene (RPS6KA3) in patients with Coffin–Lowry syndrome

“…In the present study, no mutation was found in over 60% of patients referred for mutation screening, fitting well with our previous data (2). To further determine what proportion of these patients has a mutation in RSK2 that has not been detected, we have investigated, by western blot analysis, in vitro kinase assay, cell lines from 15 patients, in whom no mutation was previously identified by SSCP analysis.…”

“…No consistent relationship between specific mutations and the severity of the disease or the expression of particular features has so far been found (2). Although only partial clinical records have been available, the data from our present study further support this conclusion (Table 1).…”

Mutations in the RSK2(RPS6KA3) gene cause Coffin–Lowry syndrome and nonsyndromic X‐linked mental retardation

“…Another case reported briefly in the literature details a male who was mildly delayed and worked independently as a janitor. He also had a proximally placed missense mutation (11). The mutation in this man and the brothers reported by Manouvrier-Hanu et al were located in the proximal kinase domain of the protein, which corresponds to the location of the mutation in our cases.…”

Unusual Splice-Site Mutations in the RSK2 Gene and Suggestion of Genetic Heterogeneity in Coffin-Lowry Syndrome

“…No RSK2 mutation has been detected in 66% (165/ 250) of the patients who were investigated by SSCP analysis (Delaunoy et al 2001). Even if mutations have been missed by SSCP in 27% of these patients, as suggested by the present article, 50% of patients who have no RSK2 defect remain.…”