A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia

Horvath, Anélia; Boikos, Sosipatros A.; Giatzakis, Christoforos; Robinson‐White, Audrey; Groussin, Lionel; Griffin, Kurt J.; Stein, Elizabeth; Levine, Elizabeth; Delimpasi, Georgia; Hsiao, Hui Pin; Keil, Meg; Heyerdahl, Sarah L.; Matyakhina, Ludmila; Libé, Rossella; Fratticci, Amato; Kirschner, Lawrence S.; Cramer, Kevin; Gaillard, Rolf C.; Bertagna, Xavier; Carney, J. Aidan; Bertherat, Jérôme; Bossis, Ioannis; Stratakis, Constantine A.

doi:10.1038/ng1809

Cited by 309 publications

(286 citation statements)

References 26 publications

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“…cGMP has been implicated in neuronal maturation (45)(46)(47), directional guidance of growth cones (48)(49)(50), and learning and memory tasks (51)(52)(53). Recently, Horvath et al (54) described inactivating mutations of the PDE11A gene in a condition predisposing to the development of adrenocortical hyperplasia leading to Cushing syndrome.…”

Section: Discussionmentioning

confidence: 99%

Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response

Wong

Whelan²,

Deloukas

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

139

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Cyclic nucleotide phosphodiesterases (PDEs) constitute a family of enzymes that degrade cAMP and cGMP. Intracellular cyclic nucleotide levels increase in response to extracellular stimulation by hormones, neurotransmitters, or growth factors and are downregulated through hydrolysis catalyzed by PDEs, which are therefore candidate therapeutic targets. cAMP is a second messenger implicated in learning, memory, and mood, and cGMP modulates nervous system processes that are controlled by the nitric oxide (NO)͞cGMP pathway. To investigate an association between genes encoding PDEs and susceptibility to major depressive disorder (MDD), we genotyped SNPs in 21 genes of this superfamily in 284 depressed Mexican Americans who participated in a prospective, double-blind, pharmacogenetic study of antidepressant response, and 331 matched controls. Polymorphisms in PDE9A and PDE11A were found to be associated with the diagnosis of MDD. Our data are also suggestive of the association between SNPs in other PDE genes and MDD. Remission on antidepressants was significantly associated with polymorphisms in PDE1A and PDE11A. Thus, we found significant associations with both the diagnosis of MDD and remission in response to antidepressants with SNPs in the PDE11A gene. We show here that PDE11A haplotype GAACC is significantly associated with MDD. We conclude that PDE11A has a role in the pathophysiology of MDD. This study identifies a potential CNS role for the PDE11 family. The hypothesis that drugs affecting PDE function, particularly cGMP-related PDEs, represent a treatment strategy for major depression should therefore be tested.gene association ͉ pharmacogenetics ͉ cGMP ͉ SNP ͉ Mexican American

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Section: Discussionmentioning

confidence: 99%

Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response

Wong

Whelan²,

Deloukas

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

139

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“…To date, mutations of PRKAR1A gene have been rarely found in sporadic pituitary tumors (21,22), although a reduced PRKAR1A expression resulting from increased proteasomal degradation has been described in sporadic GH-secreting tumors (10). Reduced cAMP degradation caused by mutations in PDE11A and PDE8B, coding for members of the phosphodiesterase (PDE) family, have been involved in adrenocortical hyperplasia, adenomas, and cancer as well as in testicular germ cell tumors (23,24). However, genetic variants of PDE11A4 contribute only marginally to the development of GH-secreting adenomas (25).…”

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confidence: 99%

Landscape of somatic mutations in sporadic GH-secreting pituitary adenomas

Ronchi¹,

Peverelli

Herterich

et al. 2016

European Journal of Endocrinology

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Context: Alterations in the cAMP signaling pathway are common in hormonally active endocrine tumors. Somatic mutations at GNAS are causative in 30-40% of GH-secreting adenomas. Recently, mutations affecting the USP8 and PRKACA gene have been reported in ACTH-secreting pituitary adenomas and cortisol-secreting adrenocortical adenomas respectively. However, the pathogenesis of many GH-secreting adenomas remains unclear. Aim: Comprehensive genetic characterization of sporadic GH-secreting adenomas and identification of new driver mutations. Design: Screening for somatic mutations was performed in 67 GH-secreting adenomas by targeted sequencing for GNAS, PRKACA, and USP8 mutations (nZ31) and next-generation exome sequencing (nZ36). Results: By targeted sequencing, known activating mutations in GNAS were detected in five cases (16.1%), while no somatic mutations were observed in both PRKACA and USP8. Whole-exome sequencing identified 132 protein-altering somatic mutations in 31/36 tumors with a median of three mutations per sample (range: 1-13). The only recurrent mutations have been observed in GNAS (31.4% of cases). However, seven genes involved in cAMP signaling pathway were affected in 14 of 36 samples and eight samples harbored variants in genes involved in the calcium signaling or metabolism. At the enrichment analysis, several altered genes resulted to be associated with developmental processes. No significant correlation between genetic alterations and the clinical data was observed. Conclusion: This study provides a comprehensive analysis of somatic mutations in a large series of GH-secreting adenomas. No novel recurrent genetic alterations have been observed, but the data suggest that beside cAMP pathway, calcium signaling might be involved in the pathogenesis of these tumors.

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“…Of the four possible splice variants, PDE11A4 coding starts from exon 3 and the protein (934 aa) includes, in addition to the catalytic domain (exon [14][15][16][17][18][19][20][21][22], two complete GAF domains and a putative phosphorylation site for protein kinase A and protein kinase G. PDE11A4 transcripts are particularly abundant in the prostate, but they are present also in endocrine tissues, including the adrenal cortex and pituitary (6)(7)(8). Germline inactivating or missense mutations of PDE11A gene have been identified in individuals with ACTH-independent macronodular adrenocortical hyperplasia, adrenocortical adenomas, and cancers (9)(10)(11), suggesting that these defects may confer susceptibility to the development of adrenocortical lesions. More recently, inactivating germline mutations in PDE11A have also been implicated in familial and bilateral testicular germ cell tumor susceptibility (12).…”

Section: Introductionmentioning

confidence: 99%

Analysis of genetic variants of phosphodiesterase 11A in acromegalic patients

Peverelli

Ermetici

Filopanti

et al. 2009

European Journal of Endocrinology

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Objectives: Aberrant cAMP signaling is involved in the pathogenesis of somatotropinomas. The aim of the study was to screen acromegalic patients for the presence of variants of phosphodiesterase type 11A (PDE11A) gene, which have been recently identified in adrenocortical and testicular tumors. Subjects and methods: We sequenced the PDE11A gene-coding region in 78 acromegalic patients and 110 controls. Immunohistochemistry for PDE11A was performed in a subgroup of adenomas and normal pituitary samples. Results: We found 15 nonsynonymous germline substitutions in 13 acromegalic patients (17%), i.e. 14 missense variants (Y727C in six, R804H in one, R867G in four, and M878V in three) and one truncating mutation (FS41X), with a prevalence only slightly higher than that observed in controls (14%). Immunohistochemistry revealed PDE11A expression higher in somatotropinomas than in normal somatotrophs, without significant difference between tumors with or without PDE11A variants, with the exception of two tumors (one with loss of heterozygosity (LOH) at the PDE11A locus and one with FS41X mutation) showing markedly reduced PDE11A staining. No significant differences in hormonal and clinical parameters between patients with or without PDE11A variants were observed, although patients with PDE11A changes showed a tendency to have a more aggressive tumor compared with patients with wild-type sequence (extrasellar extension in 69 vs 45%).Conclusions: This study first demonstrated the presence of PDE11A variants in a subset of acromegalic patients, which was only slightly more frequent than in controls. The normal expression of the enzyme in the majority of tumor tissues together with the lack of significant clinical phenotype suggests that these variants might only marginally contribute to the development of somatotropinomas.

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A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia

Cited by 309 publications

References 26 publications

Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response

Phosphodiesterase genes are associated with susceptibility to major depression and antidepressant treatment response

Landscape of somatic mutations in sporadic GH-secreting pituitary adenomas

Analysis of genetic variants of phosphodiesterase 11A in acromegalic patients

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