RPS6KA3 is the only gene known to be associated with CLS, and over 150 distinct inactivating mutations in this gene have so far been reported in CLS patients.
Inactivation of the growth factor-regulated S6 kinase RSK2 causes Coffin-Lowry syndrome in humans, an X-linked mental retardation condition associated with progressive skeletal abnormalities.
Since Coffin-Lowry syndrome and neonatal lactic acidosis are associated with mutations in the human homologues of Rsk2 and Pdha1 respectively, lined and stripey provide models for gene deficiencies in these disorders.
Three candidate genes in this region were investigated: the cDNA for kinase Rsk-2 involved in Coffin-Lowry syndrome, the brain-specific exon of a transcript in the DMD locus (DP140 isoform of dystrophin), and exon 18 of the glycerol kinase gene, which is specific to fetal brain transcripts.All three sequences were normal.
Because RSK2-inactivating mutations in humans lead to Coffin-Lowry syndrome, our results imply that alterations in GPCR signaling may account for some of its clinical manifestations.
In addition, a nonsense mutation in RPS6KA3 was found in one patient initially diagnosed with NS whose diagnosis was later revised to Coffin-Lowry syndrome.
Thus, Rsk2 loss-of-function, as seen in CLS, perturbs the differentiation of neural precursors into neurons, and maintains them instead as proliferating radial precursor cells, a defect that may underlie the cognitive dysfunction seen in CLS.
The ribosomal protein S6 kinase, 90 kb, polypeptide 3 gene (RPS6KA3) is responsible for Coffin-Lowry syndrome (CLS), which is characterized by intellectual disability (ID) and facial and bony abnormalities.
This partial duplication inhibits the RPS6KA3 expression, mimicking the effect of loss-of-function mutations associated with Coffin-Lowry syndrome (CLS).
CLS was recently associated with mutations in the low-density lipoprotein receptor-related protein 4 (LRP4) gene and dysregulated canonical WNT signaling.