Congenital stationary night blindness in mice - a tale of two Cacna1f mutants

Adv Exp Med Biol. 2010;664:549-58. doi: 10.1007/978-1-4419-1399-9_63.

Abstract

Background: Mutations in CACNA1F, which encodes the Ca(v)1.4 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: Ca(v)1.4 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 Ca(v)1.4 protein, and some cones surviving to drive photopic visual responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Substitution / genetics
  • Animals
  • Calcium Channels / genetics*
  • Calcium Channels, L-Type
  • Color Vision / physiology
  • Contrast Sensitivity / physiology
  • Disease Models, Animal
  • Electroretinography
  • Eye Diseases, Hereditary
  • Genetic Diseases, X-Linked
  • Humans
  • Mice
  • Mutation / genetics
  • Myopia / genetics*
  • Myopia / physiopathology
  • Night Blindness / genetics*
  • Night Blindness / physiopathology

Substances

  • Cacna1f protein, mouse
  • Calcium Channels
  • Calcium Channels, L-Type

Supplementary concepts

  • Night blindness, congenital stationary