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Congenital Stationary Night Blindness in Mice – A Tale of Two Cacna1f Mutants

  • N. Lodha
  • S. Bonfield
  • N.C. Orton
  • C.J. Doering
  • J.E. McRory
  • S.C. Mema
  • R. Rehak
  • Y. Sauvé
  • R. Tobias
  • W.K. Stell
  • N.T. Bech-Hansen
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 664)

Abstract

Background: Mutations in CACNA1F, which encodes the Cav1.4 subunit of a voltage-gated L-type calcium channel, cause X-linked incomplete congenital stationary night blindness (CSNB2), a condition of defective retinal neurotransmission which results in night blindness, reduced visual acuity, and diminished ERG b-wave. We have characterized two putative murine CSNB2 models: an engineered null-mutant, with a stop codon (G305X); and a spontaneous mutant with an ETn insertion in intron 2 of Cacna1f (nob2).

Methods: Cacna1f G305X : Adults were characterized by visual function (photopic optokinetic response, OKR); gene expression (microarray) and by cell death (TUNEL) and synaptic development (TEM). Cacna1f nob2 : Adults were characterized by properties of Cacna1f mRNA (cloning and sequencing) and expressed protein (immunoblotting, electrophysiology, filamin [cytoskeletal protein] binding), and OKR.

Results: The null mutation in Cacna1f  G305X mice caused loss of cone cell ribbons, failure of OPL synaptogenesis, ERG b-wave and absence of OKR. In Cacna1f  nob2 mice alternative ETn splicing produced ~90% Cacna1f mRNA having a stop codon, but ~10% mRNA encoding a complete polypeptide. Cacna1f nob2 mice had normal OKR, and alternatively-spliced complete protein had WT channel properties, but alternative ETn splicing abolished N-terminal protein binding to filamin.

Conclusions: Cav1.4 plays a key role in photoreceptor synaptogenesis and synaptic function in mouse retina. Cacna1f G305X is a true knockout model for human CSNB2, with prominent defects in cone and rod function. Cacna1f nob2 is an incomplete knockout model for CSNB2, because alternative splicing in an ETn element leads to some full-length Cav1.4 protein, and some cones surviving to drive photopic visual responses.

Keywords

Contrast Sensitivity Outer Plexiform Layer Ribbon Synapse Optokinetic Response Cone Bipolar Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

Supported by: FFB-Canada, CIHR, NSERC, and AHFMR.

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • N. Lodha
    • 1
  • S. Bonfield
    • 2
  • N.C. Orton
    • 1
    • 2
    • 3
  • C.J. Doering
    • 3
    • 4
  • J.E. McRory
    • 3
    • 4
  • S.C. Mema
    • 5
  • R. Rehak
    • 3
    • 4
  • Y. Sauvé
    • 6
  • R. Tobias
    • 1
    • 2
  • W.K. Stell
    • 2
    • 3
    • 7
    • 8
  • N.T. Bech-Hansen
    • 1
    • 2
    • 7
    • 9
  1. 1.Department Medical Genetics, Faculty of MedicineUniversity of CalgaryCalgaryCanada
  2. 2.Lions Centre for Retinal Degeneration ResearchUniversity of CalgaryCalgaryCanada
  3. 3.Hotchkiss Brain InstituteUniversity of CalgaryCalgaryCanada
  4. 4.Department of Physiology and BiophysicsUniversity of CalgaryCalgaryCanada
  5. 5.Department of Ophthalmology and Physiology, Hotchkiss Brain InstituteUniversity of AlbertaCalgaryCanada
  6. 6.Department of Ophthalmology and PhysiologyUniversity of AlbertaCalgaryCanada
  7. 7.Division of Ophthalmology, Department of SurgeryUniversity of CalgaryCalgaryCanada
  8. 8.Department of Cell Biology and AnatomyUniversity of CalgaryCalgaryCanada
  9. 9.Institute of Maternal and Child HealthUniversity of CalgaryCalgaryCanada

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