Cognitive impairment in Coffin–Lowry syndrome correlates with reduced  RSK2 activation

Harum, Karen H; Alemi, Lily; Johnston, Michael V.

doi:10.1212/wnl.56.2.207

Cited by 58 publications

(30 citation statements)

References 57 publications

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“…Persistent neuronal stimulation activates a cascade of molecular components that results in transcription and translation of new proteins, which strengthen and increase the number of synapses [18,22]. The RSK2 protein is directly involved in these signaling pathways [23,24]. Thus, alteration of RSK2 protein function resulting from mutations in CLS may disrupt the mechanisms necessary for the development and maintenance of new synapses in the hippocampus, a structure characterized by high synaptic activity, which is crucial for cognitive function.…”

Section: Discussionmentioning

confidence: 99%

Altered neurodevelopment associated with mutations of RSK2: a morphometric MRI study of Coffin–Lowry syndrome

et al. 2007

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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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Section: Discussionmentioning

confidence: 99%

Altered neurodevelopment associated with mutations of RSK2: a morphometric MRI study of Coffin–Lowry syndrome

et al. 2007

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“…However, no consistent relationship has been established between specific mutations and severity or expression of a distinct phenotype, suggesting that various substrates of RSK2 could be involved. For example, RSK2-mediated phosphorylation of CREB is also defective in CLS and was suggested to be associated with deficits in neurologic function in CLS patients (31). Because of p53's role in normal embryonic development, the loss of RSK2-mediated p53 phosphorylation and activation could very likely contribute to various phenotypes of CLS.…”

Section: Discussionmentioning

confidence: 99%

The p53 Protein Is a Novel Substrate of Ribosomal S6 Kinase 2 and a Critical Intermediary for Ribosomal S6 Kinase 2 and Histone H3 Interaction

Cho

Zhang

et al. 2005

Cancer Research

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The tumor suppressor p53 protein is one of the most highly connected nodes in cellular signal transduction pathways and acts as a central regulatory switch in networks controlling cell proliferation and apoptosis. It is involved in the activation of genes that maintain control over cellular responses to DNA errors such as DNA repair, chromosomal recombination, and chromosome segregation. Here we show that ribosomal S6 kinase 2 (RSK2) activates and phosphorylates p53 (Ser 15 ) in vitro and in vivo and colocalizes with p53 in the nucleus. Deficiency of p53 diminishes RSK2-mediated phosphorylation of histone H3 (Ser 10 ) and adding back p53 to p53embryonic fibroblasts restored phosphorylation of histone H3 at Ser 10 . These results show that the p53 protein is an important substrate of RSK2 and a critical intermediary in the RSK2 and histone H3 interaction. The RSK2-p53-histone H3 complex may likely contribute to chromatin remodeling and cell cycle regulation. (Cancer Res 2005; 65(9): 3596-603)

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“…Interestingly, RSK2 is the gene disrupted in Coffin -Lowry MR syndrome (CLS) 62 and CREB phosphorylation was shown to be perturbed in fibroblasts from CLS patients. 63,64 Moreover, another MR disorder associated with disruptions of the ERK/CREB pathway (Figure 2) is Rubinstein -Taybi syndrome (RTS). The gene involved in RTS was identified as CREB-binding protein (CBP), 65 known to have intrinsic histone acetyltransferase activity.…”

Section: Genetics and Pathophysiology Of Mr J Chelly Et Almentioning

confidence: 99%

Genetics and pathophysiology of mental retardation

et al. 2006

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Mental retardation (MR) is defined as an overall intelligence quotient lower than 70, associated with functional deficit in adaptive behavior, such as daily-living skills, social skills and communication. Affecting 1-3% of the population and resulting from extraordinary heterogeneous environmental, chromosomal and monogenic causes, MR represents one of the most difficult challenges faced today by clinician and geneticists. Detailed analysis of the Online Mendelian Inheritance in Man database and literature searches revealed more than a thousand entries for MR, and more than 290 genes involved in clinical phenotypes or syndromes, metabolic or neurological disorders characterized by MR. We estimate that many more MR genes remain to be identified. The purpose of this review is to provide an overview on the remarkable progress achieved over the last decade in delineating genetic causes of MR, and to highlight the emerging biological and cellular processes and pathways underlying pathogeneses of human cognitive disorders.

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Cognitive impairment in Coffin–Lowry syndrome correlates with reduced RSK2 activation

Abstract: This report suggests a correlation between human cognitive performance and cellular capacity to activate RSK2. It provides additional evidence that the CREB kinase, RSK2, and CREB phosphorylation may play important roles in human learning and memory, as they do in lower animals.

Cited by 58 publications

References 57 publications

Altered neurodevelopment associated with mutations of RSK2: a morphometric MRI study of Coffin–Lowry syndrome

Altered neurodevelopment associated with mutations of RSK2: a morphometric MRI study of Coffin–Lowry syndrome

The p53 Protein Is a Novel Substrate of Ribosomal S6 Kinase 2 and a Critical Intermediary for Ribosomal S6 Kinase 2 and Histone H3 Interaction

Genetics and pathophysiology of mental retardation

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