May 2007
Volume 48, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2007
Mutations in the Calcium-Binding Protein 4 (CABP4) Cause Autosomal Recessive Night Blindness
Author Affiliations & Notes
  • C. Zeitz
    Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland
  • B. Kloeckener-Gruissem
    Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland
  • U. Forster
    Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland
  • M. Gebhart
    Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria
  • I. Magyar
    Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland
  • Gá. Mátyás
    Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland
  • Jö. Striessnig
    Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, Innsbruck, Austria
  • W. Berger
    Division of Medical Molecular Genetics and Gene Diagnostics, Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland
  • Footnotes
    Commercial Relationships C. Zeitz, None; B. Kloeckener-Gruissem, None; U. Forster, None; M. Gebhart, None; I. Magyar, None; G. Mátyás, None; J. Striessnig, None; W. Berger, None.
  • Footnotes
    Support VELUX Foundation Grant#162, Hartmann Müller Foundation Grant#1002, Swiss National Science Foundation Grant 3100-067796, Austrian Science Fund P17159
Investigative Ophthalmology & Visual Science May 2007, Vol.48, 1663. doi:
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    • Get Citation

      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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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose:: 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.

Methods:: 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.

Results:: 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.

Conclusions:: 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.

Keywords: candidate gene analysis • inner retina dysfunction: hereditary • inner retina dysfunction: biochemistry and cell biology 
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