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.

ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions

“…CoffinLowry syndrome is an X-linked dominant disorder characterized by psychomotor and growth retardation and facial, hand, and skeletal malformations (84,210). Numerous mutations have now been identified in the rsk2 gene, most of which are predicted or have been shown to result in truncated or inactive RSK2 proteins (40,83). Fibroblasts derived from Coffin-Lowry syndrome patients have been useful in determining the function of RSK2 with respect to this human disease; however, differences found between these cells and RSK2-deficient mouse fibroblasts suggest that Coffin-Lowry syndrome may be a multivariable disease and may not be the ideal system with which to study RSK2 function.…”

Epigenetic Treatments for Cognitive Impairments

“…Mutations in the gene encoding RSK2, which has been shown to phosphorylate H3, produces Coffin-Lowry syndrome, an X-linked disorder that is associated with psychomotor retardation and physical abnormalities (Delaunoy et al, 2001;Merienne et al, 2001). In animal models, H3S10 phosphorylation and H3S10/K14 phosphoacetylation increases rapidly in the hippocampus following contextual fear conditioning, and these increases are blocked by ERK inhibition (Chwang et al, 2006).…”

Congenital disease SNPs target lineage specific structural elements in protein kinases

“…Moreover, K92 is strategically located relative to the kinase conserved E91, which positions the ATP by forming a salt bridge interaction with K72. Thus, mutation of K92 is likely to alter regulation either by decreasing catalytic activity as seen in INSR (A-D) (22), RSK2 (R-P) (23), and CYGD (F-S) (24), or constitutively activating the kinase as seen in KIT (K-E) (25). H100 (F in PKA) is located in the ␣C-␤4 loop, which anchors the flexible C-helix.…”

“…Similarly, in ZAP70 mutation of R465 to histidine results in a selective T cell defect (35), whereas mutation of the same arginine to cysteine results in T-B-SCID (36). However, D166 mutations are characterized by a severe phenotype and lack of autophosphorylation activity (37,38), and substitutions of N171 by lysine results in severe diseases such as Robinow syndrome or Coffin-Lowry syndrome (23,39). Subdomain VIII.…”