Kool M M J, Galac S, Spandauw C G, Kooistra H S, Mol J A
Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
J Vet Intern Med. 2013 Nov-Dec;27(6):1486-92. doi: 10.1111/jvim.12194. Epub 2013 Sep 20.
Cushing's syndrome or hypercortisolism is a common endocrinopathy in dogs. In approximately 15% of cases, the disorder is caused by adrenocorticotropin (ACTH)-independent hypersecretion of cortisol by an adrenocortical tumor (AT). Without other explanation, the cortisol hypersecretion has been referred to as autonomous.
To investigate whether ACTH-independent hypersecretion of cortisol may be associated with aberrant activation of the melanocortin 2 receptor (MC2R)-cyclic AMP (cAMP)-protein kinase A (PKA) pathway.
All analyses were performed on 44 cortisol-secreting ATs (14 adenomas and 30 carcinomas) derived from dogs diagnosed with ACTH-independent hypercortisolism.
Mutation analysis was performed of genes encoding the stimulatory G protein alpha subunit (GNAS), MC2R, and PKA regulatory subunit 1A (PRKAR1A) in all ATs.
Approximately one-third of all ATs harbored an activating mutation of GNAS. Missense mutations, known to result in constitutive activation, were present in codon 201 in 11 ATs, in codon 203 (1 AT), and in codon 227 (3 ATs). No functional mutations were found in MC2R and PRKAR1A.
Activation of cAMP signaling is a frequent event in canine cortisol-secreting ATs and may play a crucial role in both ACTH-independent cortisol production and tumor formation. To the best of our knowledge, this is the first report of potentially causative mutations in canine cortisol-secreting ATs.
库欣综合征或皮质醇增多症是犬类常见的内分泌疾病。在大约15%的病例中，该疾病是由肾上腺皮质肿瘤（AT）独立于促肾上腺皮质激素（ACTH）分泌过多的皮质醇所致。在没有其他解释的情况下，皮质醇分泌过多被称为自主性分泌。
研究皮质醇独立于ACTH分泌过多是否可能与促黑素细胞激素2受体（MC2R）-环磷酸腺苷（cAMP）-蛋白激酶A（PKA）途径的异常激活有关。
所有分析均针对44个分泌皮质醇的AT进行（14个腺瘤和30个癌），这些AT来自被诊断为ACTH非依赖性皮质醇增多症的犬类。
对所有AT中编码刺激性G蛋白α亚基（GNAS）、MC2R和PKA调节亚基1A（PRKAR1A）的基因进行突变分析。
所有AT中约三分之一存在GNAS激活突变。已知可导致组成性激活的错义突变存在于11个AT的第201密码子、1个AT的第203密码子和3个AT的第227密码子中。在MC2R和PRKAR1A中未发现功能性突变。
cAMP信号激活在犬分泌皮质醇的AT中是常见事件，可能在ACTH非依赖性皮质醇产生和肿瘤形成中起关键作用。据我们所知，这是关于犬分泌皮质醇的AT中潜在致病突变的首次报道。
