6533b828fe1ef96bd12886ab
RESEARCH PRODUCT
Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation
Maurizio EliaJacques ConstantH. ChaabouniSylvain BriaultMohamed HalayemAntonio M. PersicoDominique CahardSébastien RogerValentino RomanoJean Yves Le GuennecP. GuérinFrédéric LaumonnierRidha MradChristian R. AndresSébastien HolbertAhlem BelhadjFlorence MolinariLaurence Colleauxsubject
MaleCandidate geneChromosomes Artificial BacterialIndolesDNA Mutational AnalysisRegulatorChromosomal translocationautism mental retardation KCNMA1 genelarge conductance Ca(2+)-activated K(+) (BK(Ca)) channel synaptic transmission chromosomal translocationSynaptic TransmissionTranslocation GeneticPair 10CA2+-ACTIVATED K+ CHANNELSCloning MolecularChildLarge-Conductance Calcium-Activated Potassium Channel alpha SubunitsMUTATIONIn Situ HybridizationIn Situ Hybridization FluorescenceReverse Transcriptase Polymerase Chain ReactionBacterialChromosome MappingETIOLOGYPsychiatry and Mental healthArtificialKCNMA1 Gene[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]HaploinsufficiencyPsychologyChromosomes Human Pair 9POTASSIUM CHANNELSHumanPair 9Autistic Disorder; Child; Chromosome Aberrations; Chromosome Mapping; Chromosomes; Artificial; Bacterial; Chromosomes; Human; Pair 10; Chromosomes; Human; Pair 9; Cloning; Molecular; DNA Mutational Analysis; Humans; In Situ Hybridization; Fluorescence; Indoles; Intellectual Disability; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Male; Reverse Transcriptase Polymerase Chain Reaction; Synaptic Transmission; Translocation; GeneticTranslocationNeurotransmissionChromosomesFluorescenceGeneticIntellectual DisabilitymedicineHumansAutistic DisorderRELEASEChromosome AberrationsCOMPLEXChromosomes Human Pair 10MolecularAutistic Disorder; Child; Chromosome Aberrations; Chromosome Mapping; Chromosomes Artificial Bacterial; Chromosomes Human Pair 10; Chromosomes Human Pair 9; Cloning Molecular; DNA Mutational Analysis; Humans; In Situ Hybridization Fluorescence; Indoles; Intellectual Disability; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; Male; Reverse Transcriptase Polymerase Chain Reaction; Synaptic Transmission; Translocation GeneticPERVASIVE DEVELOPMENTAL DISORDERSmedicine.diseaseDevelopmental disorderINDIVIDUALSLARGE-CONDUCTANCEAutismSCREENNeuroscience[SDV.MHEP]Life Sciences [q-bio]/Human health and pathologyCloningdescription
International audience; 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+ ( BKCa) 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 BKCa channel. This activity can be enhanced in vitro by addition of a BKCa 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 BKCa channel and autistic disorder and raise the hypothesis that deficits in synaptic transmission may contribute to the physiopathology of autism and mental deficiency.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2006-01-01 |