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 a 1-subunit of an L-type Ca 2+ channel (Cav1.4a), 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 Cav1.4a. Mice lacking either Cabp4 or Cav1.4a 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.
The novel profile identified in this study suggests the existence of more than two rod pathways. The distinctive ERG feature was not observed in patients with X-linked CSNB1 and additional affected individuals with unknown molecular defect. These observations will help to discriminate autosomal recessive from X-linked recessive cases by ERG and molecular genetic analysis.
Retinal signal transmission depends on the activity of high voltage-gated l-type calcium channels in photoreceptor ribbon synapses. We recently identified a truncating frameshift mutation in the Cacna2d4 gene in a spontaneous mouse mutant with profound loss of retinal signaling and an abnormal morphology of ribbon synapses in rods and cones. The Cacna2d4 gene encodes an l-type calcium-channel auxiliary subunit of the alpha (2) delta type. Mutations in its human orthologue, CACNA2D4, were not yet known to be associated with a disease. We performed mutation analyses of 34 patients who received an initial diagnosis of night blindness, and, in two affected siblings, we detected a homozygous nucleotide substitution (c.2406C-->A) in CACNA2D4. The mutation introduces a premature stop codon that truncates one-third of the corresponding open reading frame. Both patients share symptoms of slowly progressing cone dystrophy. These findings represent the first report of a mutation in the human CACNA2D4 gene and define a novel gene defect that causes autosomal recessive cone dystrophy.
Mutations in the GRM6 gene, which encodes the metabotropic glutamate receptor 6 (mGluR6), lead to autosomal recessive congenital stationary night blindness (CSNB), which is characterized by loss of night vision due to a defect in signal transmission from photoreceptor to the adjacent ON-bipolar cells in the retina. So far, the sequence variations that have been described in six different families include nonsense, frameshift, and missense mutations. Here we investigated the impact of missense mutations in the ligand-binding domain, a conserved cysteine-rich domain, and the intracellular domain on the localization of the protein. We visualized and discriminated between surface and intracellular protein. Here we demonstrate that the wild-type (wt) protein localizes to the cell surface, and to endoplasmic reticulum (ER) and Golgi compartments. This also holds true for a mGluR6 variant containing a polymorphic, nondisease-associated amino acid exchange in the ligand-binding domain. In contrast, all disease-associated missense mutations lead to retention of the protein in the ER, while dimerization seems not to be affected. This is the first report that shows that CSNB-associated mutations in three different domains of mGluR6 abolish proper protein trafficking. We propose that the ligand-binding and the poorly characterized cysteine-rich domains, in addition to the intracellular domains, have a pivotal role in correct trafficking of metabotropic glutamate receptors to the cell surface.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.