Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Coffin-Lowry syndrome is an X-linked mental retardation disorder with dysmorphism caused by mutation of the ribosomal S6 kinase (RSK2) gene. Coffin-Lowry syndrome patients can experience unusual drop episodes whereby an abrupt loss of muscle tone and falling down can be induced by sudden, unexpected tactile or auditory stimuli. We detected a C913T (R305X) mutation in a female Coffin-Lowry syndrome patient with drop episodes. All mutations in our patient and those previously reported in patients with drop episodes result in premature truncation of the RSK2 protein in the N-terminal kinase domain or upstream of this domain.
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PMID:RSK2 gene mutations in Coffin-Lowry syndrome with drop episodes. 1566 50

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. Here we show that mice lacking RSK2 develop a progressive skeletal disease, osteopenia due to impaired osteoblast function and normal osteoclast differentiation. The phenotype is associated with decreased expression of Phex, an endopeptidase regulating bone mineralization. This defect is probably not mediated by RSK2-dependent phosphorylation of c-Fos on serine 362 in the C-terminus. However, in the absence of RSK2, c-Fos-dependent osteosarcoma formation is impaired. The lack of c-Fos phosphorylation leads to reduced c-Fos protein levels, which are thought to be responsible for decreased proliferation and increased apoptosis of transformed osteoblasts. Therefore, RSK2-dependent stabilization of c-Fos is essential for osteosarcoma formation in mice and may also be important for human osteosarcomas.
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PMID:Essential role of RSK2 in c-Fos-dependent osteosarcoma development. 1571 69

G protein-coupled receptors (GPCRs) are essential for normal central CNS function and represent the proximal site(s) of action for most neurotransmitters and many therapeutic drugs, including typical and atypical antipsychotic drugs. Similarly, protein kinases mediate many of the downstream actions for both ionotropic and metabotropic receptors. We report here that genetic deletion of p90 ribosomal S6 kinase 2 (RSK2) potentiates GPCR signaling. Initial studies of 5-hydroxytryptamine (5-HT)(2A) receptor signaling in fibroblasts obtained from RSK2 wild-type (+/+) and knockout (-/-) mice showed that 5-HT(2A) receptor-mediated phosphoinositide hydrolysis and both basal and 5-HT-stimulated extracellular signal-regulated kinase 1/2 phosphorylation are augmented in RSK2 knockout fibroblasts. Endogenous signaling by other GPCRs, including P2Y-purinergic, PAR-1-thrombinergic, beta1-adrenergic, and bradykinin-B receptors, was also potentiated in RSK2-deficient fibroblasts. Importantly, reintroduction of RSK2 into RSK2-/- fibroblasts normalized signaling, thus demonstrating that RSK2 apparently modulates GPCR signaling by exerting a "tonic brake" on GPCR signal transduction. Our results imply the existence of a novel pathway regulating GPCR signaling, modulated by downstream members of the extracellular signal-related kinase/mitogen-activated protein kinase cascade. The loss of RSK2 activity in humans leads to Coffin-Lowry syndrome, which is manifested by mental retardation, growth deficits, skeletal deformations, and psychosis. 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.
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PMID:p90 ribosomal S6 kinase 2 exerts a tonic brake on G protein-coupled receptor signaling. 1653 34

Coffin-Lowry syndrome (CLS) is an X-linked mental retardation syndrome caused by defects in the RSK2 gene. We have identified a CLS family with four patients in two generations. The patients in this family, a mother and her three children (a male and two females), all have severe mental retardation with the typical CLS phenotype. In addition, brain MRI studies on the three siblings revealed abnormalities in deep subcortical white matter, thinning of the corpus callosum, hypoplastic cerebellar vermis, and asymmetry of the lateral ventricles. The degree of severity of the MRI findings correlated with the severity of mental retardation in the patients. Extensive mutation screening was performed on the entire RSK2 gene in this family. Twenty-two exons including the intron/exon junctions were amplified by PCR and subsequently sequenced on both strands. A novel mutation, a two-nucleotide insertion (298 ins TG), was identified. The insertion creates a stop codon at codon 100, resulting in a 99 amino acid truncated RSK2 protein. All patients tested have the same mutation, and no other mutation could be found in the RSK2 gene from the proband. The mutation was confirmed by PCR/RFLP. X-chromosome inactivation assay on the female patients revealed significant skewing toward inactivation of the normal RSK2 allele. Thus, this novel mutation is likely to be responsible for the unusual clinical presentation in this family, which includes full phenotypic expression in females and unique brain MRI abnormalities. The pathological function of the mutation and genotype/phenotype correlation between the mutation and this unusual clinical presentation await further clarification.
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PMID:A novel RSK2 (RPS6KA3) gene mutation associated with abnormal brain MRI findings in a family with Coffin-Lowry syndrome. 1669 78

Coffin-Lowry Syndrome (CLS) is an X-linked syndromic form of mental retardation associated with skeletal abnormalities. It is caused by mutations of the Rsk2 gene, which encodes a growth factor regulated kinase. Gene deletion studies in mice have shown an essential role for the Rsk2 gene in osteoblast differentiation and function, establishing a causal link between Rsk2 deficiency and skeletal abnormalities of CLS. Although analyses in mice have revealed prominent expression of Rsk2 in brain structures that are essential for learning and memory, evidence at the behavioral level for an involvement of Rsk2 in cognitive function is still lacking. Here, we have examined Rsk2-deficient mice in two extensive batteries of behavioral tests, which were conducted independently in two laboratories in Zurich (Switzerland) and Orsay (France). Despite the known reduction of bone mass, all parameters of motor function were normal, confirming the suitability of Rsk2-deficient mice for behavioral testing. Rsk2-deficient mice showed a mild impairment of spatial working memory, delayed acquisition of a spatial reference memory task and long-term spatial memory deficits. In contrast, associative and recognition memory, as well as the habituation of exploratory activity were normal. Our studies also revealed mild signs of disinhibition in exploratory activity, as well as a difficulty to adapt to new test environments, which likely contributed to the learning impairments displayed by Rsk2-deficient mice. The observed behavioral changes are in line with observations made in other mouse models of human mental retardation and support a role of Rsk2 in cognitive functions.
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PMID:Deletion of the Coffin-Lowry syndrome gene Rsk2 in mice is associated with impaired spatial learning and reduced control of exploratory behavior. 1703 34

We describe three families with X-linked mental retardation, two with a deletion of a single amino acid and one with a missense mutation in the proximal domain of the RSK2(RPS6KA3) (ribosomal protein S6 kinase, 90 kDa, polypeptide 3) protein similar to mutations found in Coffin-Lowry syndrome (CLS). In two families, the clinical diagnosis had been nonsyndromic X-linked mental retardation. In the third family, although CLS had been suspected, the clinical features were atypical and the degree of intellectual disability much less than expected. These families show that strict reliance on classical clinical criteria for mutation testing may result in a missed diagnosis. A less targeted screening approach to mutation testing is advocated.
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PMID:Mutations in the RSK2(RPS6KA3) gene cause Coffin-Lowry syndrome and nonsyndromic X-linked mental retardation. 1710 Sep 96

This chapter explores some of the molecular events contributing to memory formation and how, when these events malfunction, disturbances in memory occur. After a brief discussion of signaling in the hippocampus, we will explore the topics of human mental retardation syndromes that involve disruption of these processes, including Angelman syndrome (AS), Neurofibromatosis 1 (NF1)-associated learning disorders, Coffin-Lowry syndrome (CLS), Rubinstein-Taybi syndrome (RTS), and Rett syndrome (RTT).
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PMID:Signal transduction mechanisms in memory disorders. 1716 2

Coffin-Lowry syndrome (CLS) is a rare genetic disorder characterized by craniofacial abnormalities, mental retardation, short stature, and hypotonia. Patients with CLS may present with multiple musculoskeletal abnormalities. The purpose of this study was to identify and characterize the musculoskeletal findings in 10 patients with CLS. Eight patients presented with thoracolumbar kyphosis or kyphoscoliosis, with a mean Cobb angle of 45 degrees in the coronal plane and 31 degrees of thoracolumbar kyphosis. These may be progressive and difficult to treat, needing early surgical treatment. Close follow-up of the spinal deformities is strongly recommended to document progression. Sixty percent of the patients presented with bilateral flexible and painless planovalgus deformities. Hypoplasia of the ilium and hand deformities are common but do not seem to cause any functional problems. Observation is recommended for these asymptomatic hand, foot, and pelvic findings.
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PMID:The musculoskeletal manifestations of the Coffin-Lowry syndrome. 1719 3

Coffin-Lowry Syndrome is characterized by mental retardation, skeletal abnormalities, delayed bone development, short stature, tapered fingers, large ears, orbital hypertelorism, anteverted nares, and a prominent frontal region. This inherited disorder is x-linked and is genetically mapped to the Xp22.2 chromosomal region. This report presents the dental findings of three male members of the same family: an older brother and younger identical twins; all three were first examined at age 10. The father's family came from North Africa and the mother's from Eastern Europe. In addition to the reported typical characteristics of Coffin-Lowry Syndrome, a number of specific dental findings were found in all of the brothers, namely, maxillary protrusion, open bite, two-year retardation in age of eruption, agenesis of the permanent mandibular central incisors in all of the brothers, and a marked oligodontia in the oldest. Despite difficulties in management, the dental treatment for caries and gingivitis could be completed on the brothers without sedation.
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PMID:Coffin-Lowry syndrome: findings and dental treatment. 1724 44

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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PMID:Altered neurodevelopment associated with mutations of RSK2: a morphometric MRI study of Coffin-Lowry syndrome. 1731 37


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