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A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Cav1.4 channel activation
- Source :
- Proceedings of the National Academy of Sciences of the United States of America. 102(21)
- Publication Year :
- 2005
-
Abstract
- Light stimuli produce graded hyperpolarizations of the photoreceptor plasma membrane and an associated decrease in a voltagegated calcium channel conductance that mediates release of glutamate neurotransmitter. The Ca v 1.4 channel is thought to be involved in this process. The CACNA1F gene encodes the poreforming subunit of the Ca v 1.4 channel and various mutations in CACNA1F cause X-linked incomplete congenital stationary night blindness (CSNB2). The molecular mechanism of the pathology underlying the CSNB2 phenotype remains to be established. Recent clinical investigations of a New Zealand family found a severe visual disorder that has some clinical similarities to, but is clearly distinct from, CSNB2. Here, we report investigations into the molecular mechanism of the pathology of this condition. Molecular genetic analyses identified a previously undescribed nucleotide substitution in CACNA1F that is predicted to encode an isoleucine to threonine substitution at CACNA1F residue 745. The I745T CACNA1F allele produced a remarkable approximately –30-mV shift in the voltage dependence of Ca v 1.4 channel activation and significantly slower inactivation kinetics in an expression system. These findings imply that substitution of this wild-type residue in transmembrane segment IIS6 may have decreased the energy required to open the channel. Collectively, these findings suggest that a gain-of-function mechanism involving increased Ca v 1.4 channel activity is likely to cause the unusual phenotype.
- Subjects :
- Retinal Disorder
Calcium Channels, L-Type
Genetic Linkage
Protein subunit
Molecular Sequence Data
Gene Expression
Biology
medicine.disease_cause
Pineal Gland
Night Blindness
medicine
Humans
Amino Acid Sequence
Genetics
Mutation
Multidisciplinary
Voltage-dependent calcium channel
Reverse Transcriptase Polymerase Chain Reaction
Calcium channel
Glutamate receptor
Genetic Diseases, X-Linked
Sequence Analysis, DNA
Biological Sciences
Phenotype
Cell biology
Pedigree
Transmembrane domain
Kinetics
Amino Acid Substitution
Calcium Channels
Ion Channel Gating
Microsatellite Repeats
New Zealand
Photoreceptor Cells, Vertebrate
Subjects
Details
- ISSN :
- 00278424
- Volume :
- 102
- Issue :
- 21
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....11cda740b2a1af2807796c7b5742e80a