title: Dysregulation of large-conductance Ca2+-activated K+ channel expression in nonsyndromal mental retardation due to a cereblon p.R419X mutation.
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.
authors.affiliation: Department of Pediatrics, Division of Pediatric Neurology, New York Presbyterian Hospital, Weill Cornell Medical College, New York, NY 10065, USA. joh2016@med.cornell.edu
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Higgins
authors.forename: Jin
authors.initials: J
authors.lastname: Hao
authors.forename: Barry E
authors.initials: BE
authors.lastname: Kosofsky
authors.forename: Anjali M
authors.initials: AM
authors.lastname: Rajadhyaksha
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D016022:Case-Control Studies; D018389:Codon, Nonsense; D017931:DNA Primers / Q000235:genetics; D005260:Female; D005808:Genes, Recessive; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism*; D007700:Kinetics; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008297:Male; D010447:Peptide Hydrolases / Q000235:genetics* / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C502543:CRBN protein, human; D018389:Codon, Nonsense; D017931:DNA Primers; C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases