文章：

心脏黏液瘤发展的遗传倾向

Inherited disposition to cardiac myxoma development

原文发布日期：2006-02-01

DOI: 10.1038/nrc1798

类型: Review Article

开放获取: 否

要点：

1. Cardiac myxomas and various non-cardiac neoplasms occur in people who have the autosomal-dominant disorder Carney complex, which is also characterized by spotty pigmentation of the skin and endocrinopathy.
2. Although complete penetrance is the rule, Carney complex shows a highly variable phenotype.
3. Mutations in the chromosome 17q PRKAR1A gene, which encodes the regulatory R1α subunit of protein kinase A (PKA), cause Carney complex in approximately two-thirds of affected individuals. No genotype–phenotype correlation has been established, and most mutations result in PRKAR1A haploinsufficiency through nonsense-mediated degradation of the transcribed, mutant mRNAs.
4. The contributions of loss of heterozygosity of PRKAR1A and increased PKA activity to Carney complex are unclear. Although both can occur in Carney complex tumours, analyses of human and murine tissues demonstrate that neither is required for tumorigenesis.
5. Changes in the ratio of type I to type II PKA isoenzymes are uniform features of human Carney complex tumours, as well as tumours that are found in genetically engineered mouse models of Carney complex. Such PKA isoform switching might mediate altered cell growth and tumorigenesis.
6. Mutation of the chromosome 17p MYH8 gene, which encodes perinatal myosin, results in a rare familial cardiac myxoma syndrome with features that are typical of Carney complex, except that affected individuals also suffer from the hereditary distal arthrogryposis syndrome, trismus–pseudocamptodactyly.
7. The mechanism by which PRKAR1A and MYH8 mutations foster the survival and proliferation of myxoma progenitor cells in the heart remains unknown.

要点翻译：

1. 心脏黏液瘤和各种非心脏肿瘤发生于患有常染色体显性遗传疾病Carney综合征的患者，该疾病还以皮肤斑点状色素沉着和内分泌病变为特征。
2. 尽管完全外显率是普遍规律，但Carney综合征表现出高度异质的表型。
3. 约三分之二受累个体的Carney综合征由染色体17q PRKAR1A基因突变引起，该基因编码蛋白激酶A（PKA）的调节性R1α亚基。目前尚未建立基因型-表型相关性，且大多数突变通过无义介导的突变mRNA降解导致PRKAR1A单倍体不足。
4. PRKAR1A杂合性缺失和PKA活性增高对Carney综合征的影响尚不明确。尽管这两种现象均可出现于Carney综合征肿瘤中，但对人类和小鼠组织的分析表明，它们并非肿瘤发生所必需的条件。
5. I型与II型PKA同工酶比例的改变是人类Carney综合征肿瘤以及Carney综合征基因工程小鼠模型肿瘤的一致特征。此类PKA亚型转换可能介导细胞生长改变和肿瘤发生。
6. 染色体17p MYH8基因（编码围产期肌球蛋白）突变会导致一种罕见的家族性心脏黏液瘤综合征，其特征与Carney综合征典型表现相似，但受累个体同时还患有遗传性远端关节弯曲综合征（即牙关紧闭-假性屈指畸形）。
7. PRKAR1A和MYH8突变促进心脏黏液瘤祖细胞存活和增殖的机制目前仍属未知。

英文摘要：

Carney complex is a genetic condition in which affected individuals develop benign tumours in various tissues, including the heart. Most individuals with Carney complex have a mutation in the PRKAR1A gene, which encodes the regulatory R1α subunit of protein kinase A — a significant component of the cyclic-AMP signalling pathway. Genetically engineered mutant Prkar1a mouse models show an increased propensity to develop tumours, and have established a role for R1α in initiating tumour formation and, potentially, in maintaining cell proliferation. Ongoing investigations are exploring the intersection of R1α-dependent cell signalling with other gene products such as perinatal myosin, mutation of which can also cause cardiac myxomas.

摘要翻译： 

Carney 综合征是一种遗传性疾病，患者会在包括心脏在内的多种组织中发生良性肿瘤。大多数 Carney 综合征患者携带 PRKAR1A 基因突变，该基因编码蛋白激酶 A 的调节亚基 R1α——环磷酸腺苷（cAMP）信号通路的重要组分。基因工程构建的 Prkar1a 突变小鼠模型表现出更高的肿瘤易感性，已证实 R1α 在启动肿瘤形成以及可能维持细胞增殖中的作用。目前的研究正在探索 R1α 依赖的细胞信号通路与其他基因产物（如围产期肌球蛋白）的相互作用，后者突变亦可导致心脏黏液瘤。

原文链接：

Inherited disposition to cardiac myxoma development