| First Author | Regus-Leidig H | Year | 2014 |
| Journal | PLoS One | Volume | 9 |
| Issue | 1 | Pages | e86769 |
| PubMed ID | 24466230 | Mgi Jnum | J:212726 |
| Mgi Id | MGI:5582026 | Doi | 10.1371/journal.pone.0086769 |
| Citation | Regus-Leidig H, et al. (2014) Photoreceptor degeneration in two mouse models for congenital stationary night blindness type 2. PLoS One 9(1):e86769 |
| abstractText | Light-dependent conductance changes of voltage-gated Cav1.4 channels regulate neurotransmitter release at photoreceptor ribbon synapses. Mutations in the human CACNA1F gene encoding the alpha1F subunit of Cav1.4 channels cause an incomplete form of X-linked congenital stationary night blindness (CSNB2). Many CACNA1F mutations are loss-of-function mutations resulting in non-functional Cav1.4 channels, but some mutations alter the channels' gating properties and, presumably, disturb Ca(2+) influx at photoreceptor ribbon synapses. Notably, a CACNA1F mutation (I745T) was identified in a family with an uncommonly severe CSNB2-like phenotype, and, when expressed in a heterologous system, the mutation was shown to shift the voltage-dependence of channel activation, representing a gain-of-function. To gain insight into the pathomechanism that could explain the severity of this disorder, we generated a mouse model with the corresponding mutation in the murine Cacna1f gene (I756T) and compared it with a mouse model carrying a loss-of-function mutation (DeltaEx14-17) in a longitudinal study up to eight months of age. In DeltaEx14-17 mutants, the b-wave in the electroretinogram was absent, photoreceptor ribbon synapses were abnormal, and Ca(2+) responses to depolarization of photoreceptor terminals were undetectable. In contrast, I756T mutants had a reduced scotopic b-wave, some intact rod ribbon synapses, and a strong, though abnormal, Ca(2+) response to depolarization. Both mutants showed a progressive photoreceptor loss, but degeneration was more severe and significantly enhanced in the I756T mutants compared to the DeltaEx14-17 mutants. |
