Cav1.4 IT mouse as model for vision impairment in human congenital stationary night blindness type 2

Channels (Austin). 2013 Nov-Dec;7(6):503-13. doi: 10.4161/chan.26368. Epub 2013 Sep 19.

Abstract

Mutations in the CACNA1F gene encoding the Cav1.4 Ca (2+) channel are associated with X-linked congenital stationary night blindness type 2 (CSNB2). Despite the increasing knowledge about the functional behavior of mutated channels in heterologous systems, the pathophysiological mechanisms that result in vision impairment remain to be elucidated. This work provides a thorough functional characterization of the novel IT mouse line that harbors the gain-of-function mutation I745T reported in a New Zealand CSNB2 family. (1) Electroretinographic recordings in IT mice permitted a direct comparison with human data. Our data supported the hypothesis that a hyperpolarizing shift in the voltage-dependence of channel activation-as seen in the IT gain-of-function mutant (2)-may reduce the dynamic range of photoreceptor activity. Morphologically, the retinal outer nuclear layer in adult IT mutants was reduced in size and cone outer segments appeared shorter. The organization of the outer plexiform layer was disrupted, and synaptic structures of photoreceptors had a variable, partly immature, appearance. The associated visual deficiency was substantiated in behavioral paradigms. The IT mouse line serves as a specific model for the functional phenotype of human CSNB2 patients with gain-of-function mutations and may help to further understand the dysfunction in CSNB.

Keywords: CSNB2; L-type calcium channel; channelopathies; gain-of-function; retinal.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Calcium Channels / genetics*
  • Calcium Channels / metabolism*
  • Calcium Channels, L-Type
  • Disease Models, Animal
  • Eye Diseases, Hereditary / genetics*
  • Eye Diseases, Hereditary / metabolism*
  • Eye Diseases, Hereditary / physiopathology
  • Gene Expression Regulation
  • Genetic Diseases, X-Linked / genetics*
  • Genetic Diseases, X-Linked / metabolism*
  • Genetic Diseases, X-Linked / physiopathology
  • Humans
  • Male
  • Mice
  • Myopia / genetics*
  • Myopia / metabolism*
  • Myopia / physiopathology
  • Night Blindness / genetics*
  • Night Blindness / metabolism*
  • Night Blindness / physiopathology
  • Phenotype
  • Point Mutation
  • Retinal Cone Photoreceptor Cells / metabolism
  • Retinal Rod Photoreceptor Cells / metabolism

Substances

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

Supplementary concepts

  • Night blindness, congenital stationary