Identification and characterization of a novel cyclic nucleotide phosphodiesterase gene (PDE9A) that maps to 21q22.3: alternative splicing of mRNA transcripts, genomic structure and sequence

Cyclic nucleotide-specific phosphodiesterases (PDEs) play an essential role in signal transduction by regulating the intracellular concentration of se cond messengers (cAMP and cGMP). We have identified and made an initial cha racterization of a full-length cDNA encoding a novel human cyclic nucleotid e phosphodiesterase, PDE9A. At least four different mRNA transcripts (PDE9A 1, A2, A3, A4) are produced as a result of alternative splicing of 5' exons , potentially changing the N-terminal amino acid sequences of the encoded p roteins. All these predicted proteins would contain a 3',5'-cyclic nucleoti de phosphodiesterase signature motif (Prosite no. PDOC00116). Northern blot analysis revealed several mRNA species of approximately 2.4 kb with varyin g expression patterns and intensities in most tissues examined, except bloo d. We have also isolated the mouse homolog of the human PDE9A2 mRNA transcr ipt, pde9A2. The human and mouse isoforms have 93 and 83% sequence identity at the amino acid and nucleotide levels, respectively. PDE9A was mapped Co 21q22.3, between TFF1 and D21S360. Comparison of the PDE9A 1 cDNA with the genomic sequence from the region revealed that the gene is split into 20 e xons that extend over 122 kb. Comparison of the physical map of the region and the genomic sequence further refines the mapping, with D21S113 being de rived from intron 15. Several genetic disorders map to 21q22.3, including o ne form of bipolar affective disorder. Since functional disturbances in int raneuronal signal transmission via second messengers play an important role in the pathophysiology of affective disorders, PDE9A is a strong candidate for such a role by position and function.