Photoreceptor degeneration in two mouse models for congenital stationary night blindness type 2.
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 α1F subunit of Cav1.4 channels cause an incomplete form of X-linked congenital stationary night blindness (CSNB2)....
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3897778?pdf=render |
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| author | Hanna Regus-Leidig Jenny Atorf Andreas Feigenspan Jan Kremers Marion A Maw Johann Helmut Brandstätter |
| author_facet | Hanna Regus-Leidig Jenny Atorf Andreas Feigenspan Jan Kremers Marion A Maw Johann Helmut Brandstätter |
| author_sort | Hanna Regus-Leidig |
| collection | DOAJ |
| description | 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 α1F 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 (ΔEx14-17) in a longitudinal study up to eight months of age. In ΔEx14-17 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 ΔEx14-17 mutants. |
| first_indexed | 2024-04-12T11:01:31Z |
| format | Article |
| id | doaj.art-b688b3da90ea4f36ad2ccdd470982b1a |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T11:01:31Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-b688b3da90ea4f36ad2ccdd470982b1a2022-12-22T03:35:57ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0191e8676910.1371/journal.pone.0086769Photoreceptor degeneration in two mouse models for congenital stationary night blindness type 2.Hanna Regus-LeidigJenny AtorfAndreas FeigenspanJan KremersMarion A MawJohann Helmut BrandstätterLight-dependent conductance changes of voltage-gated Cav1.4 channels regulate neurotransmitter release at photoreceptor ribbon synapses. Mutations in the human CACNA1F gene encoding the α1F 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 (ΔEx14-17) in a longitudinal study up to eight months of age. In ΔEx14-17 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 ΔEx14-17 mutants.http://europepmc.org/articles/PMC3897778?pdf=render |
| spellingShingle | Hanna Regus-Leidig Jenny Atorf Andreas Feigenspan Jan Kremers Marion A Maw Johann Helmut Brandstätter Photoreceptor degeneration in two mouse models for congenital stationary night blindness type 2. PLoS ONE |
| title | Photoreceptor degeneration in two mouse models for congenital stationary night blindness type 2. |
| title_full | Photoreceptor degeneration in two mouse models for congenital stationary night blindness type 2. |
| title_fullStr | Photoreceptor degeneration in two mouse models for congenital stationary night blindness type 2. |
| title_full_unstemmed | Photoreceptor degeneration in two mouse models for congenital stationary night blindness type 2. |
| title_short | Photoreceptor degeneration in two mouse models for congenital stationary night blindness type 2. |
| title_sort | photoreceptor degeneration in two mouse models for congenital stationary night blindness type 2 |
| url | http://europepmc.org/articles/PMC3897778?pdf=render |
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