ABSTRACT
BACKGROUND: Gene expression and protein synthesis, mediated by the transcription factor CREB (cAMP response element binding protein), play an important role in learning and memory in several species, including Drosophila, snails, and mice. Patients with the X-linked disorder Coffin-Lowry syndrome (CLS) have cognitive disabilities, distinctive features, and bony abnormalities as well as mutations in RSK2 (ribosomal S6 kinase-2), a protein kinase that activates CREB by phosphorylation at serine 133. In fibroblasts from a single patient with CLS, epidermal growth factor (EGF)-stimulated CREB phosphorylation was reduced. METHODS: The authors assessed endogenous CREB phosphorylation in a CLS fibroblast line by Western blotting and found impaired CREB phosphorylation in response to stimulation by EGF and the protein kinase C (PKC) agonist phorbol 12-myristate 13-acetate (PMA). They studied RSK2 immunoprecipitated from fibroblasts and lymphoblasts from seven patients with CLS and found a wide range in RSK2's capacity to phosphorylate the synthetic CREB-like peptide, CREBtide, after cell stimulation by PMA. RESULTS: In lymphoblasts from patients with CLS, PMA-stimulated CREBtide phosphorylation was increased 1.2- to 2.7-fold over baseline, compared to an average fourfold increase in controls. Regression analysis suggested a linear relationship between the magnitude of in vitro RSK2-mediated CREBtide phosphorylation and CLS patient intelligence level (p < 0.05). CONCLUSIONS: 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.
Subject(s)
Abnormalities, Multiple/enzymology , Cognition Disorders/enzymology , Intellectual Disability/enzymology , Ribosomal Protein S6 Kinases/metabolism , X Chromosome , Abnormalities, Multiple/physiopathology , Child , Child, Preschool , Cognition Disorders/physiopathology , Cyclic AMP Response Element-Binding Protein/metabolism , Female , Humans , Infant , Intellectual Disability/physiopathology , Male , SyndromeABSTRACT
A 5-year old girl with cerebral palsy (CP), preterm birth, postnatal aortic thrombus, and cerebellar venous infarction who is homozygous for the thrombophilic factor-V Leiden (fVL) mutation is reported. The role of hereditary thrombophilic disorders in the development of perinatal vascular lesions such as aortic thrombi, renal-vein thrombosis, venous-sinus thrombosis, and cerebral infarction is unknown. This case report brings into question a potential association between fVL, perinatal vascular lesions, perinatal stroke, and CP.
Subject(s)
Aortic Diseases/genetics , Cerebral Palsy/genetics , Coronary Thrombosis/genetics , Factor V/genetics , Homozygote , Point Mutation/genetics , Aortic Diseases/diagnostic imaging , Cerebral Palsy/diagnosis , Child, Preschool , Coronary Thrombosis/diagnostic imaging , Female , Humans , Infant, Newborn , Leukomalacia, Periventricular/pathology , Magnetic Resonance Imaging , Polymerase Chain Reaction/methods , UltrasonographyABSTRACT
Memory, the ability to store and retrieve information, is essential for learning in children. Modern neurobiology research is revealing some of the fundamental steps that encode memories within networks of neuronal synaptic connections in the brain. Somewhat different networks store verbal declarative memories and habit or procedural memories. Several biochemical steps convert short-term memories into permanent memories. These changes include activation of neurotransmitter and growth factor receptors, intracellular protein kinases, and nuclear transcription factors that stimulate gene expression of memory proteins. The proteins strengthen synaptic connections and stabilize long-term memories. Genetic defects in those pathways appear to be responsible for several human retardation and learning disability syndromes, including Coffin-Lowry syndrome and neurofibromatosis.
