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

摘要

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) Hope CI, Sharp DM, Hemara-Wahanui A, Sissingh JI, Lundon P, Mitchell EA, Maw MA, Clover GM. Clinical manifestations of a unique X-linked retinal disorder in a large New Zealand family with a novel mutation in CACNA1F, the gene responsible for CSNB2. Clin Experiment Ophthalmol 2005; 33:129 - 36; http://dx.doi.org/10.1111/j.1442-9071.2005.00987.x; PMID: 15807819 [Crossref], [PubMed], [Web of Science ®]?[Google Scholar] 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) Hemara-Wahanui A, Berjukow S, Hope CI, Dearden PK, Wu SB, Wilson-Wheeler J, Sharp DM, Lundon-Treweek P, Clover GM, Hoda JC, et al. A CACNA1F mutation identified in an X-linked retinal disorder shifts the voltage dependence of Cav1.4 channel activation. Proc Natl Acad Sci U S A 2005; 102:7553 - 8; http://dx.doi.org/10.1073/pnas.0501907102; PMID: 15897456 [Crossref], [PubMed], [Web of Science ®]?[Google Scholar]—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.