The PDE-Opathies: Diverse Phenotypes Produced by a Functionally Related Multigene Family

• Published in: Trends in genetics Vol. 37; no. 7; pp. 669 - 681
• Main Author: Bolger, Graeme B.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2021
• Subjects: cAMP; cGMP; gain-of-function mutation; gene redundancy; phosphodiesterase; gene redundancy; cGMP; gain-of-function mutation; phosphodiesterase; cAMP
• ISSN: 0168-9525
• DOI: 10.1016/j.tig.2021.03.002

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. The phosphodiesterase (PDE)--opathies are disorders caused by mutations in the 21-member family of human genes encoding enzymes that hydrolyze the cyclic nucleotides cAMP and/or cAMP. The PDEs are an important and expanding set of targets for drug development.The various PDE-opathies are remarkably diverse, with phenotypes varying from development/neoplasia (e.g., mutations in PDE8 and PDE11), to the cardiovascular system (PDE3) bone formation (PDE3 and PDE4), the visual system (PDE6), and the central nervous system (CNS) (PDE2, PDE4, PDE10 and others).The majority of PDE-opathies are produced by gain-of-function mutations.The PDE genes are highly conserved among metazoans and PDE-opathies typically are caused by mutations in conserved regulatory region(s) of the PDE proteins.The PDE-opathies provide novel insights into the functional aspects of PDE structure and enzymology, essential for further drug discovery.