Altered neurodevelopment associated with mutations of RSK2: A morphometric MRI study of Coffin-Lowry syndrome

Center for Interdisciplinary Brain Sciences Research, Stanford University School of Medicine, 401 Quarry Road, MC5795, Stanford, CA 94305-5795, USA.
Neurogenetics (Impact Factor: 2.88). 05/2007; 8(2):143-7. DOI: 10.1007/s10048-007-0080-6
Source: PubMed


Coffin-Lowry syndrome (CLS) is a rare form of X-linked mental retardation caused by mutations of the RSK2 gene, associated with cognitive impairment and skeletal malformations. We conducted the first morphometric study of CLS brain morphology by comparing brain volumes from two CLS families with healthy controls. Individuals with CLS consistently showed markedly reduced total brain volume. Cerebellum and hippocampus volumes were particularly impacted by CLS and may be associated with specific interfamilial RSK2 mutations. We provide preliminary evidence that the magnitude of hippocampus volume deviation from that of controls may predict general cognitive outcome in CLS.

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Available from: Shelli R Kesler
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    • "Currently, over 140 distinct mutations in RPS6KA3 have been reported, two-thirds of which cause the premature termination of translation of the RSK2 protein, often leading to a complete loss of function of the affected allele [Delaunoy et al., 2006; Pereira et al., 2010]. RSK2 is believed to have a regulatory function on skeletal and neural development in part by acting on CREB and ERK signaling pathways, explaining the characteristic dysmorphies seen in affected individuals [Fischer et al., 2009; Hao et al., 2004; Kesler et al., 2007; Mantamadiotis et al., 2002; Yang et al., 2004]. Waardenburg syndrome (WS) is classically generally associated with diagnostic features such as telecanthus, heterochromia iridis or partial albinism, and deafness, with an incidence of approximately 1:42,000 [Read and Newton, 1997]. "
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    ABSTRACT: We report an African-American family that was identified after the proposita was referred for diagnostic evaluation at 4½ months with a history of Hirschsprung and dysmorphic features typical of Waardenburg syndrome (WS). Family evaluation revealed that the father had heterochromidia irides and hypertelorism supporting the clinical diagnosis of WS; however, examination of the mother revealed characteristic facial and digital features of Coffin-Lowry syndrome (CLS). Molecular testing of the mother identified a novel 2 bp deletion (c.865_866delCA) in codon 289 of RPS6KA3 leading to a frame-shift and premature termination of translation 5 codons downstream (NM_004586.2:p.Gln289ValfsX5). This deletion also was identified in the proposita and her three sisters with a clinical suspicion of CLS, all of whom as carriers for this X-linked disorder had very subtle manifestations. The molecular confirmation of WS type 4 (Shah-Waardenburg; WS4) was not as straightforward. To evaluate WS types 1-4, multiple sequential molecular tests were requested, including Sanger sequencing of all exons, and deletion/duplication analysis using MLPA for PAX3, MITF, SOX10, EDN3 and EDNRB. Although sequencing did not identify any disease causing variants, MLPA identified a heterozygous deletion of the entire EDNRB in the father. This deletion was also found in the proposita and the oldest child. Since the heterozygous deletion was the only change identified in EDNRB, this family represents one of the few cases of an autosomal dominant inheritance of WS4 involving the endothelin pathway. Altogether, clinical evaluation of the family revealed one child to be positive for WS4 and two positive for CLS, while two children were positive for both diseases simultaneously (including the proposita) while another pair test negative for either disease. This kinship is an example of the coincidence of two conditions co-segregating in one family, with variable phenotypes requiring molecular testing to confirm the clinical diagnoses.
    Full-text · Article · Aug 2014 · European Journal of Medical Genetics
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    • "CLS patients have markedly reduced cerebellar and hippocampal volumes compared to healthy controls [3]. RSK2 plays a key role in this neurological disorder. "
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    ABSTRACT: Ribosomal S6 Kinase 2 (RSK2) is a member of the p90(RSK) family of serine/threonine kinases, which are widely expressed and respond to many growth factors, peptide hormones, and neurotransmitters. Loss-of function mutations in the RPS6KA3 gene, which encodes the RSK2 protein, have been implicated in Coffin-Lowry Syndrome (CLS), an X-linked mental retardation disorder associated with cognitive deficits and behavioral impairments. However, the cellular and molecular mechanisms underlying this neurological disorder are not known. Recent evidence suggests that defective DNA damage signaling might be associated with neurological disorders, but the role of RSK2 in the DNA damage pathway remains to be elucidated. Here, we show that Adriamycin-induced DNA damage leads to the phosphorylation of RSK2 at Ser227 and Thr577 in the chromatin fraction, promotes RSK2 nuclear translocation, and enhances RSK2 and Atm interactions in the nuclear fraction. Furthermore, using RSK2 knockout mouse fibroblasts and RSK2-deficient cells from CLS patients, we demonstrate that ablation of RSK2 impairs the phosphorylation of Atm at Ser1981 and the phosphorylation of p53 at Ser18 (mouse) or Ser15 (human) in response to genotoxic stress. We also show that RSK2 affects p53-mediated downstream cellular events in response to DNA damage, that RSK2 knockout relieves cell cycle arrest at the G2/M phase, and that an increased number of γH2AX foci, which are associated with defects in DNA repair, are present in RSK2-deficient cells. Taken together, our findings demonstrated that RSK2 plays an important role in the DNA damage pathway that maintains genomic stability by mediating cell cycle progression and DNA repair.
    Full-text · Article · Sep 2013 · PLoS ONE
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    • "Despite increasing insights into the cell-signalling functions in which the RSK2 kinase may be involved in, little is known about the role of RSK2 in neuronal functions in vivo and on the physiopathological mechanisms underlying cognitive dysfunction in CLS. A morphometric MRI study of individuals with CLS suggests a particularly important impact on cerebellar, temporal lobe and hippocampal volumes (Kesler et al., 2007). Our own behavioural studies of a Rsk2-null mutant mouse model of CLS (Rsk2-KO) revealed normal motor functions, but profound delay in spatial learning, severe deficits in long-term spatial memory consolidation and a selective reconsolidation deficit in object-place recognition memory, suggesting hippocampal dysfunction (Davis et al., 2010; Poirier et al., 2007). "
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    ABSTRACT: The Coffin-Lowry syndrome (CLS) is a syndromic form of intellectual disability caused by loss-of-function of the RSK2 serine/threonine kinase encoded by the rsk2 gene. Rsk2 knockout mice, a murine model of CLS, exhibit spatial learning and memory impairments, yet the underlying neural mechanisms are unknown. In the current study, we examined performance of Rsk2 knockout mice in cued, trace and contextual fear memory paradigms and identified selective deficits in the consolidation and reconsolidation of hippocampal-dependent fear memories as task difficulty and hippocampal demand increase. Electrophysiological, biochemical and electron microscopy analyses were carried out in the dentate gyrus of the hippocampus to explore potential alterations in neuronal functions and structure. In vivo and in vitro electrophysiology revealed impaired synaptic transmission, decreased network excitability and reduced AMPA and NMDA conductance in Rsk2 knockout mice. In the absence of RSK2, standard measures of short-term and long-term potentiation (LTP) were normal, however LTP-induced CREB phosphorylation and expression of the transcription factors EGR1/ZIF268 were reduced and that of the scaffolding protein SHANK3 was blocked, indicating impaired activity-dependent gene regulation. At the structural level, the density of perforated and non-perforated synapses and of multiple spine boutons was not altered, however, a clear enlargement of spine neck width and post-synaptic densities indicate altered synapse ultrastructure. These findings show that 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.
    Full-text · Article · Jun 2013 · Neurobiology of Disease
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