A cAMP-specific phosphodiesterase (PDE8B) that is mutated in adrenal hyperplasia is expressed widely in human and mouse tissues: a novel PDE8B isoform in human adrenal cortex (original) (raw)
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Nature Genetics, 2006
Phosphodiesterases (PDEs) regulate cyclic nucleotide levels. Increased cyclic AMP (cAMP) signaling has been associated with PRKAR1A or GNAS mutations and leads to adrenocortical tumors and Cushing syndrome 1-7 . We investigated the genetic source of Cushing syndrome in individuals with adrenocortical hyperplasia that was not caused by known defects. We performed genome-wide SNP genotyping, including the adrenocortical tumor DNA. The region with the highest probability to harbor a susceptibility gene by loss of heterozygosity (LOH) and other analyses was 2q31-2q35. We identified mutations disrupting the expression of the PDE11A isoform-4 gene (PDE11A) in three kindreds. Tumor tissues showed 2q31-2q35 LOH, decreased protein expression and high cyclic nucleotide levels and cAMP-responsive element binding protein (CREB) phosphorylation. PDE11A codes for a dual-specificity PDE that is expressed in adrenal cortex and is partially inhibited by tadalafil and other PDE inhibitors 8,9 ; its germline inactivation is associated with adrenocortical hyperplasia, suggesting another means by which dysregulation of cAMP signaling causes endocrine tumors.
Clinical Endocrinology, 2012
Background-Genetic aberrations in various components of cAMP signalling pathway predispose to endocrine tumors. Growing evidence has shown that mutations in the phosphodiesterases (PDEs) are involved in the predisposition to adrenocortical neoplastic conditions. Objective-Screen for genetic variations in PDE8B among patients with different types of adrenocortical tumors. Design and Subjects-Case-control study followed by functional analyses. 216 unrelated patients with different types of adrenocortical tumors and 192 healthy control individuals. Methods-Bi-directional Sanger sequencing, in vitro cell line transfection, in silico modelling. Results-Nine different PDE8B sequence changes, 6 novel and 3 previously reported, were identified in our patients and controls. Two of the variations, seen only in the patient group, showed significant potential to impair protein function, both in vitro and in silico.
European Journal of Endocrinology, 2009
ContextBilateral adrenal hyperplasias (BAHs) may be caused by mutations of genes that code for molecules that participate in cAMP signaling. Little is known about cAMP signaling in adrenal lesions associated with ACTH-independent Cushing syndrome (AICS) that do not harbor mutations in known genes.ObjectiveWe assessed the cAMP-signaling pathway by enzymatic and molecular studies.DesignSamples from 27 patients (ages 5–60 years) were studied and compared with normal adrenocortical tissue (n=4) and aldosterone-producing adenomas (APA, n=5). All samples were sequenced for GNAS, PRKAR1A, PDE11A, and PDE8B sequencing defects. cAMP levels and binding, protein kinase A, and phosphodiesterase (PDE) activities were assayed. Immunohistochemistry was used for certain studies and the phosphorylation status of CREB was studied.PatientsA total of 36 samples from patients were used.ResultsCortisol-producing adenomas (CPAs) and other lesions that were GNAS, PRKAR1A, PDE11A, and PDE8B gene mutation-ne...
Alterations of Phosphodiesterases in Adrenocortical Tumors
Frontiers in endocrinology, 2016
Alterations in the cyclic (c)AMP-dependent signaling pathway have been implicated in the majority of benign adrenocortical tumors (ACTs) causing Cushing syndrome (CS). Phosphodiesterases (PDEs) are enzymes that regulate cyclic nucleotide levels, including cyclic adenosine monophosphate (cAMP). Inactivating mutations and other functional variants in PDE11A and PDE8B, two cAMP-binding PDEs, predispose to ACTs. The involvement of these two genes in ACTs was initially revealed by a genome-wide association study in patients with micronodular bilateral adrenocortical hyperplasia. Thereafter, PDE11A or PDE8B genetic variants have been found in other ACTs, including macronodular adrenocortical hyperplasias and cortisol-producing adenomas. In addition, downregulation of PDE11A expression and inactivating variants of the gene have been found in hereditary and sporadic testicular germ cell tumors, as well as in prostatic cancer. PDEs confer an increased risk of ACT formation probably through, ...
Hormone and Metabolic Research, 2008
A variety of adrenal tumors and bilateral adrenocortical hyperplasias (BAH) leading to Cushing syndrome (CS) may be caused by aberrant cAMP signaling. We recently identified patients with a micronodular form of BAH that we have called "isolated micronodular adrenocortical disease" (iMAD) in whom CS was associated with inactivating mutations in phosphodiesterase (PDE) 11A (PDE11A). In the present study, we examined PDE11A expression in normal adrenocortical tissue, sporadic tumors, and hyperplasias without PDE11A mutations, and primary pigmented nodular adrenocortical disease (PPNAD) and adenomas from patients with PRKAR1A and a single tumor with a GNAS mutation. The total number of the tumor samples that we studied was 22. Normal human tissues showed consistent PDE11A expression. There was variable expression of PDE11A in sporadic adrenocortical hyperplasia or adenomas; PPNAD tissues from patients with PRKAR1A mutations expressed consistently high levels of PDE11A in contrast to adenomas caused by GNAS mutations. Phosphorylated CREB was the highest in tissues from patients with iMAD compared to all other forms of BAH and normal adrenal tissue. We conclude that PDE11A is expressed widely in adrenal cortex. Its expression appears to be increased in PPNAD but varies widely among other adrenocortical tumors. PRKAR1A expression appears to be higher in tissues with PDE11A defects. Finally, sequencing defects in PDE11A are associated with a high state of CREB phosphorylation, just like PRKAR1A mutations. These preliminary data suggest that these two molecules are perhaps regulated in a reverse manner in their control of cAMP signaling in adrenocortical tissues.
Phosphodiesterase 11A (PDE11A) and Genetic Predisposition to Adrenocortical Tumors
Clinical Cancer Research, 2008
Purpose-We have reported previously nonsense inactivating mutations of the phosphodiesterase 11A (PDE11A) gene in patients with micronodular adrenocortical hyperplasia and Cushing syndrome. The aim of this study is to investigate the presence of somatic or germline PDE11A mutations in various types of adrenocortical tumors: ACTH-independent macronodular adrenocortical hyperplasia (AIMAH), adrenocortical adenoma (ACA), and adrenocortical cancer (ACC).
Unraveling the molecular basis of micronodular adrenal hyperplasia
Current Opinion in Endocrinology, Diabetes and Obesity, 2008
Purpose of review-This review discusses the molecular basis of micronodular adrenal hyperplasia (MAH). It focuses on the role of genetic defects in cAMP signaling related molecules, namely PRKAR1A, GNAS, PDE11A and PDE8B in the predisposition for tumor formation. It also discusses the involvement of cAMP signaling and related pathways, and their impact on the adrenocortical phenotype formation. Recent findings-Molecular defects in the phosphodiesterases (PDE) family are the most recently discovered genetic defects predisposing to various adrenocortical tumor formation. In contrast to GNAS and PRKAR1A, defects in PDE genes are associated more frequently with incomplete penetrance. Summary-Recent findings indicate the importance of cAMP signaling for normal adrenocortical functioning and the sensitivity of the adrenal gland to subtle alterations in cAMP levels. Identifying low-penetrance mutations in more than one PDEs in patients with MAH is suggestive for a complementary role of the different PDEs in the adrenal gland, and possible involvement of other members of this gene family in adrenocortical signaling
Molecular and Cellular Endocrinology, 2009
Over the course of the last 10 years, we have studied the genetic and molecular mechanisms leading to disorders that affect the adrenal cortex, with emphasis on those that are developmental, hereditary and associated with adrenal hypoplasia or hyperplasia, multiple tumors and abnormalities in other endocrine glands. On the basis of this work, we propose an hypothesis on how adrenocortical tumors form and the importance of the cyclic AMP-dependent signaling pathway in this process. The regulatory subunit type 1-α (RIα) of protein kinase A (PKA), (the PRKAR1A gene) is mutated in most patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD). Phosphodiesterase-11A (the PDE11A gene) and-8B (the PDE8B gene) mutations were found in patients with isolated adrenal hyperplasia and Cushing syndrome, as well in patients with PPNAD. PKA effects on tumor suppression and/or development and the cell cycle are becoming clear: PKA and/or cAMP act as a coordinator of growth and proliferation in the adrenal cortex. Mouse models in which the respective genes have been knocked out see m to support this notion. Genome-wide searches for other genes responsible for adrenal tumors and related diseases are ongoing; recent evidece of the involvement of the mitochondrial oxidation pathway in adrenocortical tumorigenesis is derived from our study of rare associations such as those of disorders predisposing to adrenomedullary and related tumors (Carney triad, the dyad of paragangliomas and gastric stromal sarcomas or Carney-Stratakis syndrome, hereditary leiomyomatosis and renal cancer syndrome) which appear to be associated with adrenocortical lesions.
Cancer Research, 2006
Several types of adrenocortical tumors that lead to Cushing syndrome may be caused by aberrant cyclic AMP (cAMP) signaling. We recently identified patients with micronodular adrenocortical hyperplasia who were carriers of inactivating mutations in the 2q-located phosphodiesterase 11A (PDE11A) gene. 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. R804H and R867G were frequent among patients with adrenocortical tumors; although statistical significance was not reached, these variants affected significantly enzymatic function in vitro with variable increases in cAMP and/or cyclic guanosine 3 ¶,5 ¶-monophosphate levels in HeLa and HEK293 cells. Adrenocortical tissues carrying the R804H mutation showed 2q allelic losses and higher cyclic nucleotide levels and cAMP-responsive element binding protein phosphorylation. We conclude that missense mutations of the PDE11A gene that affect enzymatic activity in vitro are present in the general population; protein-truncating PDE11A mutations may also contribute to a predisposition to other tumors, in addition to their association with adrenocortical hyperplasia. We speculate that PDE11A genetic defects may be associated with adrenal pathology in a wider than previously suspected clinical spectrum that includes asymptomatic individuals. (Cancer Res 2006; 66(24): 11571-5)
Phosphodiesterases and adrenal cushing in mice and humans
Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et métabolisme, 2014
The majority of benign adrenal cortex lesions leading to Cushing syndrome are associated to one or another abnormality of the cAMP/cGMP-phosphodiesterase signaling pathway. Phosphodiesterases (PDEs) are key regulatory enzymes of intracellular cAMP/cGMP levels. These second messengers play important regulatory roles in controlling steroidogenesis in the adrenal. Disruption of PDEs has been associated with a number of adrenal diseases. Specifically, genetic mutations have been associated with benign adrenal lesions, leading to Cushing syndrome and/or related adrenal hyperplasias. A Genome Wide Association study, in 2006, led to the identification of mutations in 2 PDE genes: PDE8B and PDE11A; mutations in these 2 genes modulate steroidogenesis. Further human studies have identified PDE2 as also directly regulating steroidogenesis. PDE2 decreases aldosterone production. This review focuses on the most recent knowledge we have gained on PDEs and their association with adrenal steroidoge...