Disease relevance of PDE11A

• A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia [1].
• Furthermore, PDE11A expression was also detected in several human carcinomas [2].
• The present investigation of a large cohort of adrenocortical tumors suggests that PDE11A sequence defects predispose to a variety of lesions (beyond micronodular adrenocortical hyperplasia) and may contribute to the development of these tumors in the general population [3].

High impact information on PDE11A

• PDE11A codes for a dual-specificity PDE that is expressed in adrenal cortex and is partially inhibited by tadalafil and other PDE inhibitors; its germline inactivation is associated with adrenocortical hyperplasia, suggesting another means by which dysregulation of cAMP signaling causes endocrine tumors [1].
• Remission on antidepressants was significantly associated with polymorphisms in PDE1A and PDE11A [4].
• Polymorphisms in PDE9A and PDE11A were found to be associated with the diagnosis of MDD [4].
• Thus, we found significant associations with both the diagnosis of MDD and remission in response to antidepressants with SNPs in the PDE11A gene [4].
• We show here that PDE11A haplotype GAACC is significantly associated with MDD [4].

Biological context of PDE11A

• The human PDE11A gene was investigated and revealed to span > 300 kb, contain 23 exons and be mapped on chromosome 2q31 [5].
• The transcription start sites of PDE11A1, PDE11A3 and PDE11A4 were determined, and the promoter sequences were revealed [5].
• Tissue distribution studies indicate that PDE11A mRNA occurs at highest levels in skeletal muscle, prostate, kidney, liver, pituitary, and salivary glands and testis [6].
• PDE11A exhibits </=50% amino acid identity with the catalytic domains of all other PDEs, being most similar to PDE5, and has distinct biochemical properties [6].
• Thus, the PDE11A gene undergoes tissue-specific alternative splicing that generates structurally and functionally distinct gene products [7].

Anatomical context of PDE11A

• While human PDE11A3 and PDE11A4 are known to be specifically expressed in testis and prostate, respectively, PDE11A1 was mainly detected in skeletal muscle [5].
• No PDE11A protein was detected in blood vessels or cardiac myocytes [8].
• Using immunohistochemistry, there was strong PDE11A antibody staining in the glandular epithelium of the prostate and weak staining of neuronal cells within parasympathetic ganglia in the heart [8].

Associations of PDE11A with chemical compounds

• PDE11A is sensitive to the nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX) as well as zaprinast and dipyridamole, inhibitors that are generally considered relatively specific for the cGMP-selective PDEs, with IC(50) values of 49.8 microM, 12.0 microM, and 0.37 microM, respectively [6].

Other interactions of PDE11A

• Interestingly, both PRKAR1A and PDE11A gene products control the cAMP signaling pathway, which can be altered at various levels in endocrine tumors [9].

Analytical, diagnostic and therapeutic context of PDE11A

• This possibility is further supported by the detection of three distinct proteins of approximately 78, approximately 65, and approximately 56 kDa by Western blotting of human tissues for PDE11A isoforms [6].
• Molecular cloning and characterization of a distinct human phosphodiesterase gene family: PDE11A [6].
• cDNAs encoding a novel phosphodiesterase, phosphodiesterase 11A (PDE11A), were isolated by a combination of reverse transcriptase-polymerase chain reaction using degenerate oligonucleotide primers and rapid amplification of cDNA ends [7].
• We now studied the frequency of two missense substitutions, R804H and R867G, in conserved regions of the enzyme in several sets of normal controls, including 745 individuals enrolled in a longitudinal cohort study, the New York Cancer Project. In the latter, we also screened for the presence of the previously identified PDE11A nonsense mutations [10].

References