A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of CaV1.4 channel activation

Light stimuli produce graded hyperpolarizations of the photoreceptorplasma membrane and an associated decrease in a voltagegatedcalcium channel conductance that mediates release of glutamateneurotransmitter. The Cav1.4 channel is thought to be involved in this process. The CACNA1F gene encodes the poreforming subunit of the Cav1.4 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 Cav1.4 channel activation and significantly slower inactivation kinetics in an expression system.These findings imply that substitution of this wild-type residue intransmembrane segment IIS6 may have decreased the energy required to open the channel. Collectively, these findings suggest that a gain-of-function mechanism involving increased Cav1.4 channel activity is likely to cause the unusual phenotype.