Molecular Genetics of Carney Complex

Carney复合体(CNC)是一种常染色体显性遗传性疾病，其中心脏粘液瘤(最常见 原发心脏肿瘤)发生在皮肤的斑点状色素沉着，心外粘液瘤，罕见 非粘液瘤和内分泌病。我们已经证明了单倍体不足的突变 编码cAMP依赖的蛋白激酶A的R1a调节亚单位的PRKAR1A基因引起~2/3 计算机数控系统。此外，我们的prkarla+/-小鼠基因敲除复制了包括男性不育在内的几个方面的cnc 和肿瘤的发生。这两种表型的小鼠都是通过基因消融Ca-PKA催化而挽救的 亚单位，以及类似的遗传修饰物可能会改变人类的肿瘤发生。我们还展示了基因突变 编码围产期肌球蛋白的MYH8基因导致一种NC变异，在这种变异中，家族性心脏粘液瘤，皮肤斑点 在肢体痉挛的情况下会出现色素沉着和内分泌病。PRKAR1A所处的路径 MYH8基因与心脏发育和肿瘤发生可能存在交叉或协同作用 已经成立了。我们假设MYH8和PRKAR1A基因作用于分子的不同阶段和 肿瘤发生的细胞生物学途径。MYH8基因突变可能促进儿童持续到成年期 当PRKAR1A突变改变成人细胞内时，胚胎细胞可以作为肿瘤前体细胞 信号转导环境，以刺激这些前体细胞的致瘤扩张。因此，我们 建议：[1]确定在心脏发生和肿瘤发生过程中对围产期肌球蛋白的需求，[2] 确定PRKAR1 A依赖的肿瘤发生是否通过PKA活性增加而介导，以及[3] 识别突变导致人类数控的新基因。为了实现这些目标，我们将使用基因 设计了小鸡和小鼠模型，以确定Prkarla、Myh8和其他遗传修饰物如何 调节肌肉发生、心脏发育和肿瘤发生。此外，我们还将研究这些措施的作用 在肌成纤维细胞群体中的基因，以确定这一谱系对CNS的贡献。最后，我们会 还要识别新的CNC疾病基因，以定义与 PRKAR1A和MYH8。我们的研究将不仅强调心脏粘液瘤治疗的潜在靶点 也将阐明调控细胞分化和细胞分化的基本机制 这将促进各种常见心肌病的改进治疗。

Carney complex (CNC) is an autosomal dominant disorder in which cardiac myxomas (the most common primary cardiac tumor) occur in the setting of spotty pigmentation of the skin, extracardiac myxomas, rare nonmyxomatous tumors, and endocrinopathy. We have shown that haploinsufficient mutations of the PRKAR1A gene encoding the R1a regulatory subunit of cAMP-dependent protein kinase A cause ~2/3 of CNC. Moreover, our prkarla +/- mouse knockout replicates several aspects of CNC including male infertility and tumorigenesis. Both murine phenotypes are rescued by genetic ablation of the Ca PKA catalytic subunit, and similar genetic modifiers may alter human tumorigenesis. We also showed that mutation of the MYH8 gene encoding perinatal myosin causes a CNC variant in which familial cardiac myxomas, spotty skin pigmentation, and endocrinopathy occur in the setting of limb contracture. The pathways in which PRKAR1A and MYH8 could intersect or synergize to contribute to heart development and to tumorigenesis remain to be established. We hypothesize that the MYH8 and PRKAR1A genes act at different stages of a molecular and cell biologic pathway to tumorigenesis. MYH8 mutations may promote the persistence into adulthood of embryonic cells that can act as tumor progenitors while PRKAR1A mutations altering the adult intracellular signal transduction milieu to stimulate the tumorigenic expansion of these progenitors. Therefore, we propose: [1] To determine requirements for perinatal myosin during cardiogenesis and tumorigenesis, [2] To determine if PRKAR1 A-dependent tumorigenesis is mediated through increased PKA activity, and [3] To identify novel genes in whom mutations cause human CNC. To achieve these aims, we will use genetically engineered chick and mouse models to determine how prkarla, Myh8, and other genetic modifiers can regulate myogenesis, heart development and tumorigenesis. In addition, we will study the action of these genes in the myofibroblast population to determine the contribution of this lineage to CNC. Finally, we will also identify novel CNC disease genes to define additional pathogenic mechanisms intersecting with PRKAR1A and MYH8. Our research will highlight not only potential targets for treatment of cardiac myxomas and other CNC tumors but also will shed light on fundamental mechanisms regulating cell differentiation and growth that will promote improved treatments for a variety of common cardiomyopathies.