Novel mutations in the KCNQ2 gene link epilepsy to a dysfunction of the KCNQ2-calmodulin interaction
| Autor: | Samuel F. Berkovic, Sarah E. Heron, Michaella C. Richards, Bronwyn E. Grinton, A Davy, Ingrid E. Scheffer, H E Spendlove, J.C. Mulley |
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| Rok vydání: | 2004 |
| Předmět: |
Male
Potassium Channels Positional cloning DNA Mutational Analysis Biology Infant Newborn Diseases Structure-Activity Relationship Calmodulin Seizures KCNQ2 Potassium Channel Two-Hybrid System Techniques Genetics medicine Humans Benign familial neonatal seizures Genetic Testing Genetics (clinical) Ion channel Action potential initiation Epilepsy Infant Newborn Voltage-gated potassium channel medicine.disease Potassium channel Cell biology Pedigree Transmembrane domain Potassium Channels Voltage-Gated Mutation Female Online Mutation Report Protein Binding |
| Zdroj: | Journal of medical genetics. 41(3) |
| ISSN: | 1468-6244 |
| Popis: | Mutations in the voltage gated potassium channels KCNQ2 (OMIM 602235) and KCNQ3 (OMIM 602232) are associated with an autosomal dominant idiopathic epilepsy syndrome of newborns, benign familial neonatal seizures (BFNS) (OMIM 121200). BFNS is characterised by unprovoked partial seizures typically beginning when the infant is around three days old. BFNS associated genes were mapped to human chromosomes 20q13.31 and 8q24,2 which led to the identification by positional cloning of KCNQ2 as the chromosome 20 gene.3,4 KCNQ3 was subsequently identified as the 8q24 BFNS gene, based on genomic location and homology with KCNQ2.5 The potassium channels of the KCNQ gene family consist of four subunits, each with a 6 transmembrane topological organisation. KCNQ subunits, comprising KCNQ1–5, have an intracellular amino terminus, a single pore loop (P-loop) that forms the selectivity filter of the channel,6 a positively charged, voltage sensing fourth transmembrane domain (S4), and a large intracellular carboxy terminus (C-terminus). All five known KCNQ proteins can form homomeric channels, but the association of specific subunits to form heteromeric channels is restricted to certain combinations.6–10 KCNQ2 and KCNQ3 are mostly expressed in the central nervous system,3–5 where they form a heteromultimeric channel that mediates the neuronal muscarinic regulated current (M-current), also known as an M-channel (or M-type K+ channel). The M-current is a slowly activating, non-inactivating potassium conductance known to regulate neuronal excitability by determining the firing properties of neurones and their responsiveness to synaptic input.11 Because it is active at voltages near the threshold for action potential initiation, the M-current has a major impact on neuronal excitability. Since the KCNQ2/KCNQ3 ion channel plays a pivotal role in the regulation of neuronal excitability, it is not surprising that several mutations in the gene have been associated with epilepsy. The first … |
| Databáze: | OpenAIRE |
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