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首页> 外文期刊>Cellular Signalling >Heterozygous mutations in cyclic AMP phosphodiesterase-4D (PDE4D) and protein kinase A (PKA) provide new insights into the molecular pathology of acrodysostosis
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Heterozygous mutations in cyclic AMP phosphodiesterase-4D (PDE4D) and protein kinase A (PKA) provide new insights into the molecular pathology of acrodysostosis

机译：环状AMP磷酸二酯酶4D（PDE4D）和蛋白激酶A（PKA）中的杂合突变为肢端固定症的分子病理学提供了新见解

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摘要

Acrodysostosis without hormone resistance is a rare skeletal disorder characterized by brachydactyly, nasal hypoplasia, mental retardation and occasionally developmental delay. Recently, loss-of-function mutations in the gene encoding cAMP-hydrolyzing phosphodiesterase-4D (PDE4D) have been reported to cause this rare condition but the pathomechanism has not been fully elucidated. To understand the pathogenetic mechanism of PDE4D mutations, we conducted 3D modeling studies to predict changes in the binding efficacy of cAMP to the catalytic pocket in PDE4D mutants. Our results indicated diminished enzyme activity in the two mutants we analyzed (Gly673Asp and Ile678Thr; based on PDE4D4 residue numbering). Ectopic expression of PDE4D mutants in HEK293 cells demonstrated this reduction in activity,which was identified by increased cAMP levels. However, the cells from an acrodysostosis patient showed low cAMP accumulation, which resulted in a decrease in the phosphorylated cAMP Response Element-Binding Protein (pCREB)/CREB ratio. The reason for this discrepancy was due to a compensatory increase in expression levels of PDE4A and PDE4B isoforms, which accounted for the paradoxical decrease in cAMP levels in the patient cells expressing mutant isoforms with a lowered PDE4D activity. Skeletal radiographs of 10-week-old knockout (KO) rats showed that the distal part of the forelimb was shorter than in wild-type (WT) rats and that all the metacarpals and phalanges were also shorter in KO, as the name acrodysostosis implies. Like the G-protein α-stimulatory subunit and PRKAR1A, PDE4D critically regulates the cAMP signal transduction pathway and influences bone formation in a way that activity-compromising PDE4D mutations can result in skeletal dysplasia.We propose that specific inhibitory PDE4D mutations can lead to the molecular pathology of acrodysostosis without hormone resistance but that the pathological phenotype may well be dependent on an over-compensatory induction of other PDE4 isoforms that can be expected to be targeted to different signaling complexes and exert distinct effects on compartmentalized cAMP signaling.
机译：缺乏激素抵抗的肢端关节固定症是一种罕见的骨骼疾病，其特征是肢体短指，鼻发育不全，智力低下，有时发育迟缓。近来，已经报道了编码cAMP-水解磷酸二酯酶-4D（PDE4D）的基因中的功能丧失突变引起这种罕见情况，但尚未完全阐明其发病机理。为了了解PDE4D突变的发病机制，我们进行了3D建模研究，以预测cAMP与PDE4D突变体中催化口袋的结合效率的变化。我们的结果表明我们分析的两个突变体（Gly673Asp和Ile678Thr;基于PDE4D4残基编号）的酶活性降低。 PDE4D突变体在HEK293细胞中异位表达表明这种活性降低，这可通过cAMP水平升高来确定。但是，肢端固定症患者的细胞显示出低的cAMP积累，这导致磷酸化的cAMP反应元件结合蛋白（pCREB）/ CREB比率降低。这种差异的原因是由于PDE4A和PDE4B同工型的表达水平的补偿性增加，这解释了表达突变型同工型且PDE4D活性降低的患者细胞中cAMP水平的反常下降。 10周龄基因敲除（KO）大鼠的骨骼X线照片显示，前肢的远端比野生型（WT）大鼠短，并且所有的掌骨和指骨也较短，这是冠状动脉吻合术的名称所暗示的。像G蛋白α刺激亚基和PRKAR1A一样，PDE4D关键地调节cAMP信号转导途径并影响骨骼形成，从而损害活性的PDE4D突变可导致骨骼发育不良。没有激素抵抗，但病理表型可能完全依赖于其他PDE4亚型的过度代偿诱导，因此可以预期将其靶向不同的信号复合物，并对分隔的cAMP信号传导产生不同的影响。

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