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C. Zeitz, B. Kloeckener-Gruissem, U. Forster, M. Gebhart, I. Magyar, Gá. Mátyás, Jö. Striessnig, W. Berger; Mutations in the Calcium-Binding Protein 4 (CABP4) Cause Autosomal Recessive Night Blindness. Invest. Ophthalmol. Vis. Sci. 2007;48(13):1663.
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To identify the genetic defect in patients with incomplete congenital stationary night blindness (CSNB2), who are lacking CACNA1F mutations and to investigate the functional relevance of disease causing mutations.
The coding exons and flanking regions of the candidate gene CABP4 were PCR amplified and sequenced. The mRNA expression of CABP4 in blood from unaffected individuals and patients was investigated by quantitative real-time PCR (TaqMan analysis). The influence of mutations on the localization of CABP4 was analyzed by transient expression of wt and mutant myc-tagged CABP4 constructs in COS-7 cells.
Ten of our CSNB2 patients showed no mutation in CACNA1F. By applying a candidate gene approach we identified a missense (c.370C>T) and a frameshift mutation (c.800_801delAG) in CABP4 in two families. CABP4, a member of the calcium binding protein family, is located in photoreceptor synaptic terminals and directly associated with the C-terminal domain of the Cav1.4 α1-subunit. Mice lacking either Cabp4 or Cav1.4α1 display a CSNB2-like phenotype. We here show that both mutations reduce the transcript levels to 30-40% compared to the control. Localization studies in COS-7 cells over expressing the tagged wt and mutated variants revealed that the missense mutation shows a similar subcellular distribution compared to wt, while the frameshift mutation leads to mislocalization of the protein.
Our data provide evidence that mutations in CABP4 cause autosomal recessive incomplete CSNB. The expression analyses revealed that both, the reduced amount of CABP4 transcripts and the mislocalization of the protein may contribute to the signalling defect in patients.
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