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Association of a Functional Deficit of the BK_Ca Channel, a Synaptic Regulator of Neuronal Excitability, With Autism and Mental Retardation

OBJECTIVE: Autism is a complex, largely genetic psychiatric disorder. In the majority of cases, the cause of autism is not known, but there is strong evidence for a genetic etiology. To identify candidate genes, the physical mapping of balanced chromosomal aberrations is a powerful strategy, since several genes have been characterized in numerous disorders. In this study, the authors analyzed a balanced reciprocal translocation arising de novo in a subject with autism and mental retardation. METHOD: The authors performed the physical mapping of the balanced 9q23/10q22 translocation by fluorescent in situ hybridization experiments using bacterial artificial chromosome clones covering the areas of interest. RESULTS: Findings revealed that the KCNMA1 gene, which encodes the alpha-subunit of the large conductance Ca²⁺-activated K⁺ (BK_Ca) channel, a synaptic regulator of neuronal excitability, is physically disrupted. Further molecular and functional analyses showed the haploinsufficiency of this gene as well as decreased activity of the coded BK_Ca channel. This activity can be enhanced in vitro by addition of a BK_Ca channel opener (BMS-204352). Further mutational analyses on 116 autistic subjects led to the identification of an amino acid substitution located in a highly conserved domain of the protein not found in comparison subjects. CONCLUSIONS: These results suggest a possible association between a functional defect of the BK_Ca channel and autistic disorder and raise the hypothesis that deficits in synaptic transmission may contribute to the physiopathology of autism and mental deficiency.

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