Abstract
A nonsense mutation (R419X) in the human cereblon gene [mutation (mut) CRBN] causes a mild type of autosomal recessive nonsyndromal mental retardation (ARNSMR). CRBN, a cytosolic protein, regulates the assembly and neuronal surface expression of large-conductance Ca(2+)-activated K(+) channels (BK(Ca)) in brain regions involved in memory and learning. Using the real-time quantitative polymerase chain reaction, we show that mut CRBN disturbs the development of adult brain BK(Ca) isoforms. These changes are predicted to result in BK(Ca) channels with a higher intracellular Ca(2+) sensitivity, faster activation, and slower deactivation kinetics. Such alterations may contribute to cognitive impairments in patients with mild ARNSMR.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing
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Adult
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Base Sequence
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Brain / metabolism
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Case-Control Studies
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Codon, Nonsense*
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DNA Primers / genetics
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Female
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Genes, Recessive
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Humans
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Intellectual Disability / genetics*
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Intellectual Disability / metabolism*
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Kinetics
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Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / chemistry
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Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / genetics
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Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / metabolism*
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Male
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Peptide Hydrolases / genetics*
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Peptide Hydrolases / metabolism*
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Polymerase Chain Reaction
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Ubiquitin-Protein Ligases
Substances
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Adaptor Proteins, Signal Transducing
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CRBN protein, human
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Codon, Nonsense
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DNA Primers
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KCNMA1 protein, human
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Large-Conductance Calcium-Activated Potassium Channel alpha Subunits
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Ubiquitin-Protein Ligases
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Peptide Hydrolases