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RSK2 and the Coffin-Lowry Syndrome 

RSK2 and the Coffin-Lowry Syndrome
Chapter:
RSK2 and the Coffin-Lowry Syndrome
Author(s):

Anne Schneider

, Jean-Pierre Delaunoy

, and André Hanauer

DOI:
10.1093/med/9780199934522.003.0146
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date: 04 March 2021

Coffin–Lowry syndrome (CLS) is a syndromic form of X-linked intellectual deficiency, which is characterized in male patients by psychomotor and growth retardation, and various skeletal anomalies. Typical facial changes and specific clinical and radiological signs in the hand are useful aids in the diagnosis. CLS is caused by mutations in the RPS6KA3 gene located at Xp22.2, which encodes RSK2, a growth-factor-regulated protein kinase. RSK2 belongs to the 90 kDa RSK family, which includes four highly related members in humans, RSK1 through -4, encoded by distinct genes. RSKs act at the distal end of the Ras/mitogen-activated protein kinase (MAPK) signaling pathway, phosphorylate, and activate a variety of nuclear and cytoplasmic proteins in response to a broad range of cellular perturbations, including stimulation with growth factors and neurotransmitters. RSK family members have been implicated in several important cellular events, including proliferation and differentiation, response to stress, and apoptosis. It is still unclear whether the four proteins regulate distinct physiological functions or whether their functions are in large part overlapping. However, RSK2 has specifically been implicated in phosphorylation of some cytosolic and nuclear substrates including transcription factors. RSK2-deficient mice have been created that exhibit growth retardation and learning and spatial memory deficits. They represent powerful tools to elucidate the molecular mechanisms that generate the CLS phenotype. Recent evidence showed that Rsk2-KO in mice leads, for instance, to an altered level of expression of numerous genes in the hippocampus and In particular to up-regulation of the gria2 gene (encoding the glutamate AMPA receptor subunit GLUR2) expression associated with a reduced AMPA receptor-mediated neurotransmission. RPS6KA3 gene mutations in patients with CLS are extremely heterogeneous and lead to premature termination of translation and/or to loss of phosphotransferase activity. No obvious correlation is observed between the position or type of the RSK2 mutations and the severity or particular clinical features of CLS. However, significantly milder disease was noted in a few cases with missense mutations, leaving a residual RSK2 kinase activity.

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