Cav1.4 IT mouse as model for vision impairment in human congenital stationary night blindness type 2.
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.
Medical University Vienna; Centre for Physiology and Pharmacology; Department of Neurophysiology and Pharmacology; Vienna, Austria.
Dagmar
D
Knoflach
University of Iowa; Department of Molecular Physiology & Biophysics; Iowa City, IA USA; University of Iowa; Department of Biochemistry; Iowa City, IA USA.
Vasily
V
Kerov
University of Innsbruck; Institute of Pharmacy, Pharmacology and Toxicology; Center for Chemistry and Biomedicine; Innsbruck, Austria.
Simone B
SB
Sartori
Medical University Innsbruck; Division of Physiology; Innsbruck, Austria.
Gerald J
GJ
Obermair
University of Innsbruck; Institute of Pharmacy, Pharmacology and Toxicology; Center for Chemistry and Biomedicine; Innsbruck, Austria.
Claudia
C
Schmuckermair
University of Iowa; Department of Molecular Physiology & Biophysics; Iowa City, IA USA.
Xiaoni
X
Liu
University of Tübingen; Institute for Ophthalmic Research; Centre for Ophthalmology; Division of Ocular Neurodegeneration; Tübingen, Germany.
Vithiyanjali
V
Sothilingam
University of Tübingen; Institute for Ophthalmic Research; Centre for Ophthalmology; Division of Ocular Neurodegeneration; Tübingen, Germany.
Marina
M
Garcia Garrido
University of Iowa; Department of Biochemistry; Iowa City, IA USA.
Sheila A
SA
Baker
University of Veterinary Medicine; Vetcore; Vienna, Austria.
Martin
M
Glösmann
Medical University Vienna; Centre for Physiology and Pharmacology; Department of Neurophysiology and Pharmacology; Vienna, Austria.
Klaus
K
Schicker
University of Tübingen; Institute for Ophthalmic Research; Centre for Ophthalmology; Division of Ocular Neurodegeneration; Tübingen, Germany.
Mathias
M
Seeliger
University of Iowa; Department of Molecular Physiology & Biophysics; Iowa City, IA USA.
Amy
A
Lee
Medical University Vienna; Centre for Physiology and Pharmacology; Department of Neurophysiology and Pharmacology; Vienna, Austria.
Alexandra
A
Koschak
D000818:Animals; D001522:Behavior, Animal; D015220:Calcium Channels / Q000235:genetics* / Q000378:metabolism*; D020746:Calcium Channels, L-Type; D004195:Disease Models, Animal; D015785:Eye Diseases, Hereditary / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D005786:Gene Expression Regulation; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D009216:Myopia / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D009755:Night Blindness / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D010641:Phenotype; D017354:Point Mutation; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism
C480684:Cacna1f protein, mouse; D015220:Calcium Channels; D020746:Calcium Channels, L-Type
CSNB2; L-type calcium channel; channelopathies; gain-of-function; retinal