Retinitis pigmentosa: impact of different Pde6a point mutations on the disease phenotype
Retinitis pigmentosa: impact of different Pde6a point mutations on the disease phenotype
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DOI：
10.1093/hmg/ddv275
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发表时间：
2015-10-01
影响因子：
3.5
通讯作者：
Paquet-Durand, Francois
中科院分区：
文献类型：
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作者：
Sothilingam, Vithiyanjali;Garrido, Marina Garcia;Paquet-Durand, Francois
PDE 6A基因突变可导致视杆细胞变性和致盲性疾病视网膜色素变性（RP）。虽然已经描述了许多致病性PDE 6A突变，但对其对复合杂合情况的影响以及不同致病等位基因的潜在相互作用知之甚少。在这里，我们使用了一种新的小鼠模型的Pde 6a R562 W突变与现有的线携带V685 M突变，以产生复合杂合Pde 6a V685 M/R562 W动物，完全同源的情况下，人类RP。我们比较了这些复合杂合子小鼠与纯合子V685 M和R562 W突变体的感光细胞变性的进展，此外还与D 670 G系（已知具有相对温和的表型）进行了比较。我们研究了PDE 6A的表达，环磷酸鸟苷的积累，钙蛋白酶和半胱天冬酶的活性，在体内视网膜功能和形态，以及感光细胞的死亡和存活。该分析证实了不同Pde 6a突变的严重性，并表明复合杂合突变体的行为类似于相应纯合情况的中间体。具体地，四种不同Pde 6a情况的严重性可以通过光感受器退化的速度分类：V685 M（最快）> V685 M/R562 W> R562 W> D 670 G（最慢）。虽然钙蛋白酶活性在所有四种突变体中强烈增加，但胱天蛋白酶活性没有增加。这指向非凋亡性细胞死亡的执行，并可能导致治疗干预的新靶点的鉴定。对于个体RP患者，我们的研究可能有助于预测Pde 6a相关视网膜变性的时间进程，从而有助于定义临床干预的机会窗口。
Mutations in the PDE6A gene can cause rod photoreceptors degeneration and the blinding disease retinitis pigmentosa (RP). While a number of pathogenic PDE6A mutations have been described, little is known about their impact on compound heterozygous situations and potential interactions of different disease-causing alleles. Here, we used a novel mouse model for the Pde6a R562W mutation in combination with an existing line carrying the V685M mutation to generate compound heterozygous Pde6a V685M/R562W animals, exactly homologous to a case of human RP. We compared the progression of photoreceptor degeneration in these compound heterozygous mice with the homozygous V685M and R562W mutants, and additionally with the D670G line that is known for a relatively mild phenotype. We investigated PDE6A expression, cyclic guanosine mono-phosphate accumulation, calpain and caspase activity, in vivo retinal function and morphology, as well as photoreceptor cell death and survival. This analysis confirms the severity of different Pde6a mutations and indicates that compound heterozygous mutants behave like intermediates of the respective homozygous situations. Specifically, the severity of the four different Pde6a situations may be categorized by the pace of photoreceptor degeneration: V685M (fastest) > V685M/R562W > R562W > D670G (slowest). While calpain activity was strongly increased in all four mutants, caspase activity was not. This points to the execution of non-apoptotic cell death and may lead to the identification of new targets for therapeutic interventions. For individual RP patients, our study may help to predict time-courses for Pde6a-related retinal degeneration and thereby facilitate the definition of a window-of-opportunity for clinical interventions.