BZI Pharma LLC, Birmingham, AL 35203-1872, USA.
Trends Genet. 2021 Jul;37(7):669-681. doi: 10.1016/j.tig.2021.03.002. Epub 2021 Apr 5.
The phosphodiesterase (PDE)-opathies, an expanding set of disorders caused by germline mutations in cyclic nucleotide PDEs, present an intriguing paradox. The enzymes encoded by the PDE family all hydrolyze cAMP and/or cGMP, but mutations in different family members produce very divergent phenotypes. Three interacting factors have been shown recently to contribute to this phenotypic diversity: (i) the 21 genes encode over 80 different isoforms, using alternative mRNA splicing and related mechanisms; (ii) the various isoforms have different regulatory mechanisms, mediated by their unique amino-terminal regulatory domains; (iii) the isoforms differ widely in their pattern of tissue expression. These mechanisms explain why many PDE-opathies are gain-of-function mutations and how they exemplify uniqueness and redundancy within a multigene family.
磷酸二酯酶（PDE）病是一组由环核苷酸 PDE 种系突变引起的不断扩展的疾病，其表现出一种有趣的悖论。PDE 家族所编码的酶均水解 cAMP 和/或 cGMP，但不同家族成员的突变会产生非常不同的表型。最近有研究表明，有三个相互作用的因素促成了这种表型多样性：（i）这 21 个基因通过选择性剪接和相关机制编码超过 80 种不同的亚型；（ii）各种亚型具有不同的调节机制，由其独特的氨基末端调节结构域介导；（iii）亚型在组织表达模式上差异很大。这些机制解释了为什么许多 PDE 病是功能获得性突变，以及它们如何在多基因家族中体现独特性和冗余性。
