CNRS UMR6247, Génétique Reproduction et Développement, Clermont Université, Aubière, France.
PLoS Genet. 2010 Jun 10;6(6):e1000980. doi: 10.1371/journal.pgen.1000980.
Carney complex (CNC) is an inherited neoplasia syndrome with endocrine overactivity. Its most frequent endocrine manifestation is primary pigmented nodular adrenocortical disease (PPNAD), a bilateral adrenocortical hyperplasia causing pituitary-independent Cushing's syndrome. Inactivating mutations in PRKAR1A, a gene encoding the type 1 alpha-regulatory subunit (R1alpha) of the cAMP-dependent protein kinase (PKA) have been found in 80% of CNC patients with Cushing's syndrome. To demonstrate the implication of R1alpha loss in the initiation and development of PPNAD, we generated mice lacking Prkar1a specifically in the adrenal cortex (AdKO). AdKO mice develop pituitary-independent Cushing's syndrome with increased PKA activity. This leads to autonomous steroidogenic genes expression and deregulated adreno-cortical cells differentiation, increased proliferation and resistance to apoptosis. Unexpectedly, R1alpha loss results in improper maintenance and centrifugal expansion of cortisol-producing fetal adrenocortical cells with concomitant regression of adult cortex. Our data provide the first in vivo evidence that loss of R1alpha is sufficient to induce autonomous adrenal hyper-activity and bilateral hyperplasia, both observed in human PPNAD. Furthermore, this model demonstrates that deregulated PKA activity favors the emergence of a new cell population potentially arising from the fetal adrenal, giving new insight into the mechanisms leading to PPNAD.
卡尼综合征（CNC）是一种具有内分泌过度活跃的遗传性肿瘤综合征。其最常见的内分泌表现为原发性色素性结节性肾上腺皮质疾病（PPNAD），这是一种双侧肾上腺皮质增生导致的垂体非依赖性库欣综合征。在 80%患有库欣综合征的 CNC 患者中，发现了编码 cAMP 依赖性蛋白激酶（PKA）的 1 型α调节亚基（R1alpha）的 PRKAR1A 基因失活突变。为了证明 R1alpha 缺失在 PPNAD 的起始和发展中的作用，我们生成了特异性在肾上腺皮质中缺乏 Prkar1a 的小鼠（AdKO）。AdKO 小鼠会发展为垂体非依赖性库欣综合征，伴有 PKA 活性增加。这导致自主甾体生成基因表达和肾上腺皮质细胞分化失调、增殖增加和抗凋亡。出乎意料的是，R1alpha 的缺失导致产生皮质醇的胎儿肾上腺皮质细胞的不当维持和离心性扩张，同时伴有成年皮质的退化。我们的数据提供了第一个体内证据，证明 R1alpha 的缺失足以诱导自主肾上腺活性亢进和双侧增生，这两种情况均见于人类 PPNAD。此外，该模型表明，PKA 活性失调有利于新的细胞群体的出现，这些细胞可能来自胎儿肾上腺，为导致 PPNAD 的机制提供了新的见解。
