Abstract
Mutations in genes encoding either components of the phototransduction cascade or proteins presumably involved in signaling from photoreceptors to adjacent second-order neurons have been shown to cause congenital stationary night blindness (CSNB). Sequence alterations in CACNA1F lead to the incomplete type of CSNB (CSNB2), which can be distinguished by standard electroretinography (ERG). CSNB2 is associated with a reduced rod b-wave, a substantially reduced cone a-wave, and a reduced 30-Hz flicker ERG response. CACNA1F encodes the alpha 1-subunit of an L-type Ca2+ channel (Cav1.4 alpha ), which is specific to photoreceptors and is present at high density in the synaptic terminals. Ten of our patients with CSNB2 showed no mutation in CACNA1F. To identify the disease-causing mutations, we used a candidate-gene approach. CABP4, a member of the calcium-binding protein (CABP) family, is located in photoreceptor synaptic terminals and is directly associated with the C-terminal domain of the Cav1.4 alpha . Mice lacking either Cabp4 or Cav1.4 alpha display a CSNB2-like phenotype. Here, we report for the first time that mutations in CABP4 lead to autosomal recessive CSNB. Our studies revealed homozygous and compound heterozygous mutations in two families. We also show that these mutations reduce the transcript levels to 30%-40% of those in controls. This suggests that the reduced amount of CABP4 is the reason for the signaling defect in these patients.