Dysregulation of large-conductance Ca2+-activated K+ channel expression in nonsyndromal mental retardation due to a cereblon p.R419X mutation
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- Higgins, J.J., Hao, J., Kosofsky, B.E. et al. Neurogenetics (2008) 9: 219. doi:10.1007/s10048-008-0128-2
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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 Ca2+-activated K+ channels (BKCa) 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 BKCa isoforms. These changes are predicted to result in BKCa channels with a higher intracellular Ca2+ sensitivity, faster activation, and slower deactivation kinetics. Such alterations may contribute to cognitive impairments in patients with mild ARNSMR.