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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 7. Functional comparison of human and murine subjects affected by the I745T mutation. Ganzfeld ERG recordings from a normal subject (left) and a patient with incomplete CSNB carrying the CACNA1F mutation I745T (center left) were redrawn form the original records (ref. 3). They correlate rather well with the murine data of wt (C57BL/6N; center right) and IT mice (right). The set of records follows the human ERG diagnostic standard as issued by the International Society for Clinical Electrophysiology of Vision (ISCEV; www.iscev.org/standards). From top to bottom, traces in each column represent the scotopic single flash response, the scotopic mixed response, the photopic single flash response, and the photopic 30 Hz flicker ERG. The murine records were obtained with identical paradigms.
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Figure 7: Figure 7. Functional comparison of human and murine subjects affected by the I745T mutation. Ganzfeld ERG recordings from a normal subject (left) and a patient with incomplete CSNB carrying the CACNA1F mutation I745T (center left) were redrawn form the original records (ref. 3). They correlate rather well with the murine data of wt (C57BL/6N; center right) and IT mice (right). The set of records follows the human ERG diagnostic standard as issued by the International Society for Clinical Electrophysiology of Vision (ISCEV; www.iscev.org/standards). From top to bottom, traces in each column represent the scotopic single flash response, the scotopic mixed response, the photopic single flash response, and the photopic 30 Hz flicker ERG. The murine records were obtained with identical paradigms.

Mentions: The Ganzfeld ERG recordings, both dark adapted (scotopic) and light adapted (photopic), suggest that there is a very close match between rod and cone system responses in CSNB2 patients carrying the I745T mutation1 and the IT mouse line (Fig. 7). The functional pattern in both resembles a form of incomplete CSNB; rod and cone single flash responses as well as the flicker ERG were typically altered. The particular feature in I745T mutants, presumably associated with the gain-of-function nature of the disorder, is that the negative components of the scotopic standard flash response are smaller than those found in other CSNB types, but on the other hand a distinct remaining b-wave component is present. The comparison with the human data clearly underlines that the IT mouse line is a specific model for the functional phenotype seen in respective patients.


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 7. Functional comparison of human and murine subjects affected by the I745T mutation. Ganzfeld ERG recordings from a normal subject (left) and a patient with incomplete CSNB carrying the CACNA1F mutation I745T (center left) were redrawn form the original records (ref. 3). They correlate rather well with the murine data of wt (C57BL/6N; center right) and IT mice (right). The set of records follows the human ERG diagnostic standard as issued by the International Society for Clinical Electrophysiology of Vision (ISCEV; www.iscev.org/standards). From top to bottom, traces in each column represent the scotopic single flash response, the scotopic mixed response, the photopic single flash response, and the photopic 30 Hz flicker ERG. The murine records were obtained with identical paradigms.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Figure 7. Functional comparison of human and murine subjects affected by the I745T mutation. Ganzfeld ERG recordings from a normal subject (left) and a patient with incomplete CSNB carrying the CACNA1F mutation I745T (center left) were redrawn form the original records (ref. 3). They correlate rather well with the murine data of wt (C57BL/6N; center right) and IT mice (right). The set of records follows the human ERG diagnostic standard as issued by the International Society for Clinical Electrophysiology of Vision (ISCEV; www.iscev.org/standards). From top to bottom, traces in each column represent the scotopic single flash response, the scotopic mixed response, the photopic single flash response, and the photopic 30 Hz flicker ERG. The murine records were obtained with identical paradigms.
Mentions: The Ganzfeld ERG recordings, both dark adapted (scotopic) and light adapted (photopic), suggest that there is a very close match between rod and cone system responses in CSNB2 patients carrying the I745T mutation1 and the IT mouse line (Fig. 7). The functional pattern in both resembles a form of incomplete CSNB; rod and cone single flash responses as well as the flicker ERG were typically altered. The particular feature in I745T mutants, presumably associated with the gain-of-function nature of the disorder, is that the negative components of the scotopic standard flash response are smaller than those found in other CSNB types, but on the other hand a distinct remaining b-wave component is present. The comparison with the human data clearly underlines that the IT mouse line is a specific model for the functional phenotype seen in respective patients.

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