Photoreceptor Degeneration in Two Mouse Models for Congenital Stationary Night Blindness Type 2
Photoreceptor Degeneration in Two Mouse Models for Congenital Stationary Night Blindness Type 2
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DOI：
10.1371/journal.pone.0086769
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发表时间：
2014-01-21
期刊：
影响因子：
3.7
通讯作者：
Brandstaetter, Johann Helmut
中科院分区：
文献类型：
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作者：
Regus-Leidig, Hanna;Atorf, Jenny;Brandstaetter, Johann Helmut
电压门控 Ca(v)1.4 通道的光依赖性电导变化调节感光带突触处的神经递质释放。编码 Cav1.4 通道 α 1F 亚基的人类 CACNA1F 基因突变会导致不完全形式的 X 连锁先天性静止性夜盲症 (CSNB2)。许多 CACNA1F 突变是功能丧失突变，导致 Cav1.4 通道无功能，但某些突变会改变通道的门控特性，并且可能会干扰光感受器带状突触处的 Ca2+ 流入。值得注意的是，在一个具有异常严重的 CSNB2 样表型的家族中发现了 CACNA1F 突变 (I745T)，并且当在异源系统中表达时，该突变被证明可以改变通道激活的电压依赖性，代表功能获得。为了深入了解可以解释这种疾病严重程度的病理机制，我们生成了一个小鼠 Cacna1f 基因 (I756T) 具有相应突变的小鼠模型，并在长达 8 个月龄的纵向研究中将其与携带功能丧失突变 (Delta Ex14-17) 的小鼠模型进行了比较。在Delta Ex14-17突变体中，视网膜电图中的b波缺失，光感受器带状突触异常，并且检测不到对光感受器末端去极化的Ca2+反应。相比之下，I756T 突变体的暗位 b 波减少，一些完整的杆状带状突触，以及对去极化的强烈但异常的 Ca2+ 反应。两种突变体均表现出进行性光感受器丧失，但与 Delta Ex14-17 突变体相比，I756T 突变体的退化更为严重且显着增强。
Light-dependent conductance changes of voltage-gated Ca(v)1.4 channels regulate neurotransmitter release at photoreceptor ribbon synapses. Mutations in the human CACNA1F gene encoding the alpha 1F 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 Ca2+ 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 (Delta Ex14-17) in a longitudinal study up to eight months of age. In Delta Ex14-17 mutants, the b-wave in the electroretinogram was absent, photoreceptor ribbon synapses were abnormal, and Ca2+ 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, Ca2+ 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 Delta Ex14-17 mutants.