Mutations of the gene encoding the protein kinase A type I-α regulatory subunit in patients with the Carney complex
Mutations of the gene encoding the protein kinase A type I-α regulatory subunit in patients with the Carney complex
复制标题
DOI：
10.1038/79238
复制
发表时间：
2000-09-01
期刊：
影响因子：
30.8
通讯作者：
Stratakis, CA
中科院分区：
文献类型：
--
作者：
Kirschner, LS;Carney, JA;Stratakis, CA
Carney complex （CNC）是一种多发性肿瘤综合征，其特征为皮肤色素斑点、心脏和其他黏液瘤、内分泌肿瘤和沙质黑色素神经鞘瘤（1-5）。CNC是一种常染色体显性遗传性状，相关基因已定位于2p16和17q22-24（参考文献6,7）。由于其与McCune-Albright综合征（5,8）的相似性以及其他特征，例如对内分泌信号的矛盾反应(9)，与环核苷酸依赖性信号传导相关的基因被认为是导致CNC的候选基因（参考文献10）。在数控家族映射到17q。我们在编码蛋白激酶A调节亚基1- α (Rl α)的基因（PRKAR1A）附近检测到杂合性缺失（LOH），包括其5'区域内的多态性位点。随后，我们确定了PRKAR1A编码区具有相同突变的三种不相关的类型。对其他病例的分析显示，在一个散发的CNC病例中发现了相同的突变，在其他三个家族中发现了不同的突变，包括一个分离的遗传性心脏黏液瘤。对CNC肿瘤中PKA活性的分析表明，与非CNC肿瘤相比，CNC肿瘤中的PKA活性降低，但camp刺激的活性增加。我们得出结论，PRKAR1A（一种明显的肿瘤抑制基因）的种系突变是导致该疾病患者的CNC表型的原因。
Carney complex (CNC) is a multiple neoplasia syndrome characterized by spotty skin pigmentation, cardiac and other myxomas, endocrine tumours and psammomatous melanotic schwannomas(1-5). CNC is inherited as an autosomal dominant trait and the genes responsible have been mapped to 2p16 and 17q22-24 (refs 6,7). Because of its similarities to the McCune-Albright syndrome(5,8) and other features, such as paradoxical responses to endocrine signals(9), genes implicated in cyclic nucleotide-dependent signalling have been considered candidates for causing CNC (ref. 10). In CNC families mapping to 17q. we detected loss of heterozygosity (LOH) in the vicinity of the gene (PRKAR1A) encoding protein kinase A regulatory subunit 1-alpha (Rl alpha), including a polymorphic site within its 5' region. We subsequently identified three unrelated kindreds with an identical mutation in the coding region of PRKAR1A. Analysis of additional cases revealed the same mutation in a sporadic case of CNC, and different mutations in three other families, including one with isolated inherited cardiac myxomas. Analysis of PKA activity in CNC tumours demonstrated a decreased basal activity, but an increase in cAMP-stimulated activity compared with non-CNC tumours, We conclude that germline mutations in PRKAR1A, an apparent tumour-suppressor gene, are responsible for the CNC phenotype in a subset of patients with this disease.