Zilbermint Mihail, Stratakis Constantine A
Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Curr Opin Endocrinol Diabetes Obes. 2015 Jun;22(3):157-62. doi: 10.1097/MED.0000000000000149.
Cushing syndrome caused by cortisol-producing adrenal adenomas is a rare condition, associated with high morbidity due to weight gain, diabetes mellitus, osteoporosis, hypertension, muscle weakness, mood disturbance and others. The first gene to be identified as causative of Cushing syndrome was PRKAR1A. We present an update on protein kinase A (PKA) defects and Cushing syndrome.
The cyclic AMP-dependent PKA catalytic subunit alpha (PRKACA) hotspot point mutation (c.617A > C [p.Leu206Arg]), leading to an increase of basal PKA activity, and formation of cortisol-producing adenoma has been frequently shown to cause the most common form of adrenocorticotropic hormone-independent Cushing syndrome.
Somatic PRKACA mutations have been found in up to 50% of patients with adrenal adenomas. Germline PRKACA amplification was also seen in bilateral adrenal hyperplasias. PRKACA activation was associated with higher cortisol levels, smaller tumor size and overt Cushing syndrome. This breakthrough is expected to improve our understanding of how PKA defects lead to Cushing syndrome and may spearhead the development of new, molecularly designed therapies.
由分泌皮质醇的肾上腺腺瘤引起的库欣综合征是一种罕见疾病，因体重增加、糖尿病、骨质疏松、高血压、肌肉无力、情绪障碍等导致高发病率。首个被确定为库欣综合征致病原因的基因是PRKAR1A。我们介绍蛋白激酶A（PKA）缺陷与库欣综合征的最新情况。
环磷酸腺苷依赖性PKA催化亚基α（PRKACA）热点点突变（c.617A>C [p.Leu206Arg]），导致基础PKA活性增加，并形成分泌皮质醇的腺瘤，常被证明会引起最常见的促肾上腺皮质激素非依赖性库欣综合征。
高达50%的肾上腺腺瘤患者中发现了体细胞PRKACA突变。在双侧肾上腺增生中也发现了种系PRKACA扩增。PRKACA激活与较高的皮质醇水平、较小的肿瘤大小和明显的库欣综合征有关。这一突破有望增进我们对PKA缺陷如何导致库欣综合征的理解，并可能引领新的分子设计疗法的发展。
