Phosphodiesterase 11A (PDE11A) Gene Defects in Patients with ACTH-Independent Macronodular Adrenal Hyperplasia (AIMAH): Functional Variants May Contribute to Genetic Susceptibility of Bilateral Adrenal Tumors

被引：61

作者：

Vezzosi, Delphine ^{[1
,2
,3
]}

Libe, Rossella ^{[1
,2
,4
]}

Baudry, Camille ^{[1
,2
,4
]}

Rizk-Rabin, Marthe ^{[1
,2
]}

Horvath, Anelia ^{[5
]}

Levy, Isaac ^{[5
]}

Rene-Corail, Fernande ^{[1
]}

Ragazzon, Bruno ^{[1
,2
]}

Stratakis, Constantine A. ^{[5
,6
]}

Vandecasteele, Gregoire ^{[7
,8
]}

Bertherat, Jerome ^{[1
,2
,4
]}

机构：

[1] INSERM, Unite 1016, CNRS, UMR 8104,Inst Cochin, F-75014 Paris, France

[2] Univ Paris 05, Fac Med Paris 5, F-75005 Paris, France

[3] Hop Larrey, Dept Endocrinol, F-31480 Toulouse, France

[4] Hop Cochin, Reference Ctr Rare Adrenal Dis, AP HP, Dept Endocrinol, F-75014 Paris, France

[5] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol Genet, NIH, Bethesda, MD 20892 USA

[6] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Pediat Endocrinol Interinst Training Program, NIH, Bethesda, MD 20892 USA

[7] INSERM, UMR S 769, Labex Lab Excellence Res Medicat & Innovat Therap, F-92296 Chatenay Malabry, France

[8] Univ Paris Sud, Inst Federatif Rech 141, F-92296 Chatenay Malabry, France

来源：

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM | 2012年 / 97卷 / 11期

基金：

美国国家卫生研究院;

关键词：

REGULATORY SUBUNIT; CUSHINGS-SYNDROME; MUTATIONS; PROTEIN; EXPRESSION; FREQUENT; IDENTIFICATION; ASSOCIATION; RECEPTORS; PDE8B;

D O I：

10.1210/jc.2012-2275

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Context: Phosphodiesterases (PDEs) are key regulatory enzymes of intracellular cAMP levels. PDE11A function has been linked to predisposition to adrenocortical tumors. Objective: The aim of the study was to study the PDE11A gene in a large cohort of patients with ACTH-independent macronodular adrenal hyperplasia (AIMAH) and in control subjects. Design: The PDE11A entire coding region was sequenced in 46 patients with AIMAH and 192 controls. Two variants found in AIMAH patients were transiently expressed in HEK 293 and adrenocortical H295R cells for further functional studies. Results: The frequency of all PDE11A variants was significantly higher among patients with AIMAH (28%) compared to controls (7.2%) (P = 5 x 10(-5)). Transfection of the two PDE11A variants found in AIMAH patients only (D609N or M878V) showed that cAMP levels were higher, after forskolin stimulation, in cells transfected with the PDE11A mutants, compared to cells transfected with the wild-type PDE11A in HEK 293 cells (P < 0.05). Moreover, transfection with mutants PDE11A increased transcriptional activity of a cAMP-response element reporter construct compared to wild-type PDE11A in HEK 293 cells (P < 0.0004 for D609N and P < 0.003 for M878V) and in the adrenocortical H295R cells (P < 0.05 for D609N and M878V). In addition, analysis of cAMP levels in intact living culture cells by fluorescence resonance energy transfer probes showed increased cAMP in forskolin-treated cells transfected with PDE11A variants compared with wild-type PDE11A (P < 0.05). Conclusion: We conclude that PDE11A genetic variants may increase predisposition to AIMAH. (J Clin Endocrinol Metab 97: E2063-E2069, 2012)

引用

页码：E2063 / E2069

页数：7

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