Jia, S., Muto, A., Orisme, W., Henson, H.E., Parupalli, C., Ju, B., Baier, H., and Taylor, M.R. (2014) Zebrafish Cacna1fa is required for cone photoreceptor function and synaptic ribbon formation. Hum. Mol. Genet.. 23(11):2981-94.
Mutations in the human CACNA1F gene cause incomplete congenital stationary night blindness type 2 (CSNB2), a non-progressive, clinically heterogeneous retinal
disorder. However, the molecular mechanisms underlying CSNB2 have not been fully explored. Here, we describe the positional
cloning of a blind zebrafish mutant, wait until dark (wud), which encodes a zebrafish homolog of human CACNA1F. We identified two zebrafish cacna1f paralogs and showed that the cacna1fa transcript (the gene mutated in wud) is expressed exclusively in the photoreceptor layer. We demonstrated that Cacna1fa localizes at the photoreceptor synapse
and is absent from wud mutants. Electroretinograms revealed abnormal cone photoreceptor responses from wud mutants, indicating a defect in synaptic transmission. Although there are no obvious morphological differences, we found
that wud mutants lacked synaptic ribbons and that wud is essential for the development of synaptic ribbons. We found that Ribeye, the most prominent synaptic ribbon protein, was
less abundant and mislocalized in adult wud mutants. In addition to cloning wud, we identified synaptojanin 1 (synj1) as the defective gene in slacker (slak), a blind mutant with floating synaptic ribbons. We determined that Cacna1fa was expressed in slak photoreceptors and that Synj1 was initially expressed wud photoreceptors, but was absent by 5 days postfertilization. Collectively, our data demonstrate that Cacna1fa is essential
for cone photoreceptor function and synaptic ribbon formation and reveal a previously unknown yet critical role of L-type
voltage-dependent calcium channels in the expression and/or distribution of synaptic ribbon proteins, providing a new model
to study the clinical variability in human CSNB2 patients.