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Mechanisms of mutant PDE6 proteins underlying retinal diseases

机译：视网膜疾病下面的突变PDE6蛋白的机制

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Mutations in PDE6 genes encoding the effector enzymes in rods and cones underlie severe retinal diseases including retinitis pigmentosa (RP), autosomal dominant congenital stationary night blindness (adCSNB), and achromatopsia (ACHM). Here we examined a spectrum of pathogenic missense mutations in PDE6 using the system based on co-expression of cone PDE6C with its specialized chaperone AIPL1 and the regulatory P gamma subunit as a potent co-chaperone. We uncovered two mechanisms of PDE6C mutations underlying ACHM: (a) folding defects leading to expression of catalytically inactive proteins and (b) markedly diminished ability of P gamma to co-chaperone mutant PDE6C proteins thereby dramatically reducing the levels of functional enzyme. The mechanism of the Rambusch adCSNB associated with the H258N substitution in PDE6B was probed through the analysis of the model mutant PDE6C-H262N. We identified two interrelated deficits of PDE6C-H262N: disruption of the inhibitory interaction of P gamma with mutant PDE6C that markedly reduced the ability of P gamma to augment the enzyme folding. Thus, we conclude that the Rambusch adCSNB is triggered by low levels of the constitutively active PDE6. Finally, we examined PDE6C-L858V, which models PDE6B-L854V, an RP-linked mutation that alters the protein isoprenyl modification. This analysis suggests that the type of prenyl modifications does not impact the folding of PDE6, but it modulates the enzyme affinity for its trafficking partner PDE6D. Hence, the pathogenicity of PDE6B-L854V likely arises from its trafficking deficiency. Taken together, our results demonstrate the effectiveness of the PDE6C expression system to evaluate pathogenicity and elucidate the mechanisms of PDE6 mutations in retinal diseases.
机译：编码视杆细胞和视锥细胞效应酶的PDE6基因突变是严重视网膜疾病的基础，包括色素性视网膜炎（RP）、常染色体显性先天性静止性夜盲（adCSNB）和色盲（ACHM）。在这里，我们研究了PDE6中的致病性错义突变谱，该系统基于cone PDE6C及其特异性伴侣AIPL1和作为有效共伴侣的调节性Pγ亚基的共表达。我们发现了导致ACHM的PDE6C突变的两种机制：（a）折叠缺陷导致催化非活性蛋白的表达；（b）P-γ与伴侣突变PDE6C蛋白的协同作用显著减弱，从而显著降低了功能酶的水平。通过对模型突变体PDE6C-H262N的分析，探讨了与PDE6B中H258N取代相关的Rambusch adCSNB的机制。我们发现了PDE6C-H262N的两个相互关联的缺陷：P-γ与突变型PDE6C的抑制性相互作用的中断，这显著降低了P-γ增强酶折叠的能力。因此，我们得出结论，Rambusch adCSNB是由低水平的组成性活性PDE6触发的。最后，我们检测了PDE6C-L858V，它模拟了PDE6B-L854V，这是一种RP连锁突变，可改变蛋白质异戊二烯基修饰。该分析表明，丙炔基修饰的类型不会影响PDE6的折叠，但会调节其与贩运伙伴PDE6D的酶亲和力。因此，PDE6B-L854V的致病性可能来自其运输缺陷。总之，我们的结果证明了PDE6C表达系统在评估视网膜疾病致病性和阐明PDE6突变机制方面的有效性。

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