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

Dagmar Knoflach; Vasily Kerov; Simone B Sartori; Gerald J Obermair; Claudia Schmuckermair; Xiaoni Liu; Vithiyanjali Sothilingam; Marina Garcia Garrido; Sheila A Baker; Martin Glösmann; Klaus Schicker; Mathias Seeliger; Amy Lee; Alexandra Koschak

doi:10.4161/chan.26368

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

Journal article

Open access

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

Dagmar Knoflach, Vasily Kerov, Simone B Sartori, Gerald J Obermair, Claudia Schmuckermair, Xiaoni Liu, Vithiyanjali Sothilingam, Marina Garcia Garrido, Sheila A Baker, Martin Glösmann, …

Channels (Austin, Tex.), Vol.7(6), pp.503-513

11/2013

DOI: 10.4161/chan.26368

PMCID: PMC4042485

PMID: 24051672

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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.

Calcium Channels - metabolism

Night Blindness - metabolism

Humans

Calcium Channels, L-Type

Male

Retinal Rod Photoreceptor Cells - metabolism

Myopia - metabolism

Behavior, Animal

Genetic Diseases, X-Linked - genetics

Calcium Channels - genetics

Night Blindness - genetics

Genetic Diseases, X-Linked - physiopathology

Disease Models, Animal

Eye Diseases, Hereditary - physiopathology

Gene Expression Regulation

Genetic Diseases, X-Linked - metabolism

Eye Diseases, Hereditary - genetics

Myopia - genetics

Point Mutation

Phenotype

Animals

Myopia - physiopathology

Night Blindness - physiopathology

Mice

Retinal Cone Photoreceptor Cells - metabolism

Eye Diseases, Hereditary - metabolism

Details

Title: Subtitle: Cav1.4 IT mouse as model for vision impairment in human congenital stationary night blindness type 2
Creators: Dagmar Knoflach - Medical University Vienna; Centre for Physiology and Pharmacology; Department of Neurophysiology and Pharmacology; Vienna, Austria
Vasily Kerov - University of Iowa; Department of Molecular Physiology & Biophysics; Iowa City, IA USA; University of Iowa; Department of Biochemistry; Iowa City, IA USA
Simone B Sartori - University of Innsbruck; Institute of Pharmacy, Pharmacology and Toxicology; Center for Chemistry and Biomedicine; Innsbruck, Austria
Gerald J Obermair - Medical University Innsbruck; Division of Physiology; Innsbruck, Austria
Claudia Schmuckermair - University of Innsbruck; Institute of Pharmacy, Pharmacology and Toxicology; Center for Chemistry and Biomedicine; Innsbruck, Austria
Xiaoni Liu - University of Iowa; Department of Molecular Physiology & Biophysics; Iowa City, IA USA
Vithiyanjali Sothilingam - University of Tübingen; Institute for Ophthalmic Research; Centre for Ophthalmology; Division of Ocular Neurodegeneration; Tübingen, Germany
Marina Garcia Garrido - University of Tübingen; Institute for Ophthalmic Research; Centre for Ophthalmology; Division of Ocular Neurodegeneration; Tübingen, Germany
Sheila A Baker - University of Iowa; Department of Biochemistry; Iowa City, IA USA
Martin Glösmann - University of Veterinary Medicine; Vetcore; Vienna, Austria
Klaus Schicker - Medical University Vienna; Centre for Physiology and Pharmacology; Department of Neurophysiology and Pharmacology; Vienna, Austria
Mathias Seeliger - University of Tübingen; Institute for Ophthalmic Research; Centre for Ophthalmology; Division of Ocular Neurodegeneration; Tübingen, Germany
Amy Lee - University of Iowa; Department of Molecular Physiology & Biophysics; Iowa City, IA USA
Alexandra Koschak - Medical University Vienna; Centre for Physiology and Pharmacology; Department of Neurophysiology and Pharmacology; Vienna, Austria
Resource Type: Journal article
Publication Details: Channels (Austin, Tex.), Vol.7(6), pp.503-513
Publisher: United States
DOI: 10.4161/chan.26368
PMID: 24051672
PMCID: PMC4042485
ISSN: 1933-6950
eISSN: 1933-6969
Grant note: EY020542 / NEI NIH HHS R01 EY020542 / NEI NIH HHS DC009433 / NIDCD NIH HHS HL87120 / NHLBI NIH HHS R55 DC009433 / NIDCD NIH HHS P 24079 / Austrian Science Fund FWF P 22528 / Austrian Science Fund FWF P30 DC010362 / NIDCD NIH HHS R01 DC009433 / NIDCD NIH HHS DC010362 / NIDCD NIH HHS R01 HL087120 / NHLBI NIH HHS W 1206 / Austrian Science Fund FWF
Language: English
Date published: 11/2013
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Biochemistry and Molecular Biology; University College Courses; Ophthalmology and Visual Sciences
Record Identifier: 9984024547502771

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