A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Cav1.4 channel activation

Proc Natl Acad Sci U S A. 2005 May 24;102(21):7553-8. doi: 10.1073/pnas.0501907102. Epub 2005 May 16.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution / genetics
  • Calcium Channels / metabolism*
  • Calcium Channels, L-Type / genetics*
  • Gene Expression*
  • Genetic Diseases, X-Linked / genetics*
  • Genetic Diseases, X-Linked / metabolism
  • Genetic Diseases, X-Linked / pathology
  • Genetic Linkage
  • Humans
  • Ion Channel Gating / genetics*
  • Ion Channel Gating / physiology
  • Kinetics
  • Microsatellite Repeats / genetics
  • Molecular Sequence Data
  • Mutation / genetics
  • New Zealand
  • Night Blindness / genetics*
  • Night Blindness / metabolism
  • Night Blindness / pathology
  • Pedigree
  • Photoreceptor Cells, Vertebrate / metabolism*
  • Pineal Gland / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Analysis, DNA


  • CACNA1F protein, human
  • Calcium Channels
  • Calcium Channels, L-Type