title: A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Cav1.4 channel activation.
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.
authors.affiliation: Biochemistry Department, University of Otago, P.O. Box 56, Dunedin, Aotearoa New Zealand.
authors.forename: Ariana
authors.initials: A
authors.lastname: Hemara-Wahanui
authors.forename: Stanislav
authors.initials: S
authors.lastname: Berjukow
authors.forename: Carolyn I
authors.initials: CI
authors.lastname: Hope
authors.forename: Peter K
authors.initials: PK
authors.lastname: Dearden
authors.forename: Shu-Biao
authors.initials: SB
authors.lastname: Wu
authors.forename: Jane
authors.initials: J
authors.lastname: Wilson-Wheeler
authors.forename: Dianne M
authors.initials: DM
authors.lastname: Sharp
authors.forename: Patricia
authors.initials: P
authors.lastname: Lundon-Treweek
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Clover
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Hoda
authors.forename: Jörg
authors.initials: J
authors.lastname: Striessnig
authors.forename: Rainer
authors.initials: R
authors.lastname: Marksteiner
authors.forename: Steffen
authors.initials: S
authors.lastname: Hering
authors.forename: Marion A
authors.initials: MA
authors.lastname: Maw
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D015220:Calcium Channels / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics*; D015870:Gene Expression; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008040:Genetic Linkage; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics* / Q000502:physiology; D007700:Kinetics; D018895:Microsatellite Repeats / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009520:New Zealand; D009755:Night Blindness / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D020419:Photoreceptor Cells, Vertebrate / Q000378:metabolism*; D010870:Pineal Gland / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: C113330:CACNA1F protein, human; D015220:Calcium Channels; D020746:Calcium Channels, L-Type