, Volume 9, Issue 3, pp 219–223 | Cite as

Dysregulation of large-conductance Ca2+-activated K+ channel expression in nonsyndromal mental retardation due to a cereblon p.R419X mutation

  • Joseph J. Higgins
  • Jin Hao
  • Barry E. Kosofsky
  • Anjali M. Rajadhyaksha
Short Communication


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.


Large-conductance calcium-activated potassium channel alpha subunits Alternative splicing Cereblon protein, human Mental retardation, nonsyndromic, autosomal recessive, 2A protein, human Reverse transcriptase polymerase chain reaction 

Supplementary material

10048_2008_128_MOESM1_ESM.gif (30 kb)
Fig. S1

Abridged pedigree of a family with autosomal recessive nonsyndromal mental retardation caused by a nonsense mutation (p.R419X) in the CRBN gene. Black circle (female) and square (male) symbols represent individuals with mild mental retardation. Consanguineous mating is joined by double bars uniting individuals. Immortalized lymphoblastoid cell lines from four affected individuals in generation VI and one affected individual in generation VII were analyzed in this study. The number on the upper right side of the symbol represents the identification number assigned in previous publications [9, 10]. The number on the lower right of the symbol is the age of the affected individual (GIF 29.9 kb)

10048_2008_128_MOESM2_ESM.tif (118 kb)
High resolution image file (TIF 118 kb)


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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Joseph J. Higgins
    • 1
  • Jin Hao
    • 1
  • Barry E. Kosofsky
    • 2
  • Anjali M. Rajadhyaksha
    • 2
  1. 1.Department of Pediatrics, Division of Pediatric Neurology, New York Presbyterian HospitalWeill Cornell Medical CollegeNew YorkUSA
  2. 2.Department of Pediatrics, Division of Pediatric Neurology, Neurology and Neuroscience, New York Presbyterian HospitalWeill Cornell Medical CollegeNew YorkUSA

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