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

Knoflach D, Kerov V, Sartori SB, Obermair GJ, Schmuckermair C, Liu X, Sothilingam V, Garcia Garrido M, Baker SA, Glösmann M, Schicker K, Seeliger M, Lee A, Koschak A - Channels (Austin) (2013)

Bottom Line: 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.Morphologically, the retinal outer nuclear layer in adult IT mutants was reduced in size and cone outer segments appeared shorter.The associated visual deficiency was substantiated in behavioral paradigms.

View Article: PubMed Central - PubMed

Affiliation: Medical University Vienna; Centre for Physiology and Pharmacology; Department of Neurophysiology and Pharmacology; Vienna, Austria.

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.

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Figure 1. Functional assessment of wt and IT mouse retinas in vivo based on ERG. Left column: Representative Ganzfeld-ERG intensity series for dark-adapted (scotopic, [A]) and light-adapted (photopic, [B]) responses in wt (black) and IT mice (gray). Right column: Quantitative evaluation of the scotopic (A) and photopic (B) b-wave amplitude data for the entire group (wt, n = 2; IT, n = 4).
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Figure 1: Figure 1. Functional assessment of wt and IT mouse retinas in vivo based on ERG. Left column: Representative Ganzfeld-ERG intensity series for dark-adapted (scotopic, [A]) and light-adapted (photopic, [B]) responses in wt (black) and IT mice (gray). Right column: Quantitative evaluation of the scotopic (A) and photopic (B) b-wave amplitude data for the entire group (wt, n = 2; IT, n = 4).

Mentions: Ganzfeld ERG recordings allow both dark adapted (scotopic) measurements to study rod-driven activity and light adapted (photopic) recordings to obtain information about the contribution of the cone system.16 We found that adult IT animals very well matched their human CSNB2 counterparts in terms of the functional pattern resembling incomplete CSNB. Both rod and cone single flash responses (Fig. 1A and B) as well as the flicker ERG amplitude (not shown) were reduced. In contrast, the negative components of the scotopic standard flash response were smaller than those found in other CSNB models, and a minute but distinct positive peak indicated a remaining b-wave component. However, identical differences were found in patients carrying the exact same mutation.1 The IT mouse line is therefore a representative model for human CSNB2 caused by the I745T mutation.


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

Knoflach D, Kerov V, Sartori SB, Obermair GJ, Schmuckermair C, Liu X, Sothilingam V, Garcia Garrido M, Baker SA, Glösmann M, Schicker K, Seeliger M, Lee A, Koschak A - Channels (Austin) (2013)

Figure 1. Functional assessment of wt and IT mouse retinas in vivo based on ERG. Left column: Representative Ganzfeld-ERG intensity series for dark-adapted (scotopic, [A]) and light-adapted (photopic, [B]) responses in wt (black) and IT mice (gray). Right column: Quantitative evaluation of the scotopic (A) and photopic (B) b-wave amplitude data for the entire group (wt, n = 2; IT, n = 4).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4042485&req=5

Figure 1: Figure 1. Functional assessment of wt and IT mouse retinas in vivo based on ERG. Left column: Representative Ganzfeld-ERG intensity series for dark-adapted (scotopic, [A]) and light-adapted (photopic, [B]) responses in wt (black) and IT mice (gray). Right column: Quantitative evaluation of the scotopic (A) and photopic (B) b-wave amplitude data for the entire group (wt, n = 2; IT, n = 4).
Mentions: Ganzfeld ERG recordings allow both dark adapted (scotopic) measurements to study rod-driven activity and light adapted (photopic) recordings to obtain information about the contribution of the cone system.16 We found that adult IT animals very well matched their human CSNB2 counterparts in terms of the functional pattern resembling incomplete CSNB. Both rod and cone single flash responses (Fig. 1A and B) as well as the flicker ERG amplitude (not shown) were reduced. In contrast, the negative components of the scotopic standard flash response were smaller than those found in other CSNB models, and a minute but distinct positive peak indicated a remaining b-wave component. However, identical differences were found in patients carrying the exact same mutation.1 The IT mouse line is therefore a representative model for human CSNB2 caused by the I745T mutation.

Bottom Line: 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.Morphologically, the retinal outer nuclear layer in adult IT mutants was reduced in size and cone outer segments appeared shorter.The associated visual deficiency was substantiated in behavioral paradigms.

View Article: PubMed Central - PubMed

Affiliation: Medical University Vienna; Centre for Physiology and Pharmacology; Department of Neurophysiology and Pharmacology; Vienna, Austria.

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.

Show MeSH
Related in: MedlinePlus