Relevance to Autism

A small subset of patients with Coffin-Lowry syndrome have also presented with autism (Zeniou et al., 2002) or transient autistic behavior (Manouvrier-Hanu et al., 1999), implicating RPS6KA3 as a syndromic ASD gene. On a related note, an ASD case had previously been identified who had also been given a provisional diagnosis of Coffin-Lowry syndrome (Bryson et al., 1988). More recently, a de novo loss-of-function variant in the RPS6KA3 gene was identified in an ASD case from the Simons Simplex Collection (O'Roak et al., 2012).

Molecular Function

This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains 2 non-identical kinase catalytic domains and phosphorylates various substrates, including members of the mitogen-activated kinase (MAPK) signalling pathway. The activity of this protein has been implicated in controlling cell growth and differentiation. Mutations in this gene are associated with Coffin-Lowry syndrome (CLS) [MIM:303600], a X-linked mental retardation associated with facial and digital dysmorphisms, progressive skeletal malformations, growth retardation, hearing deficit and paroxysmal movement disorders, as well as with mental retardation, X-linked 19 (MRX19) [MIM:300844], a non-syndromic form of mild-to-moderate mental retardation.

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Model Summary

RSK2 loss-of-function is associated in the dentate gyrus with multi-level alterations that encompass modifications of glutamate receptor channel properties, synaptic transmission, plasticity-associated gene expression and spine morphology, providing novel insights into the mechanisms contributing to cognitive impairments in CLS.

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