Molecular Genetics of Carney Complex

描述(申请人提供)：Carney复合体(CNC)是一种常染色体显性遗传性疾病，心脏粘液瘤(最常见的原发心脏肿瘤)发生在皮肤斑点状色素沉着、心外粘液瘤、罕见的非粘液瘤肿瘤和内分泌疾病的背景下。我们已经证明，编码cAMP依赖的蛋白激酶A的R1a调节亚基的PRKAR1A基因的单倍体不足突变导致了~2/3的CnC。此外，我们的prkar1a+/-小鼠基因敲除复制了cnc的几个方面，包括男性不育和肿瘤发生。这两种小鼠的表型都可以通过基因消融Ca PKA催化亚单位来挽救，类似的遗传修饰物可能会改变人类的肿瘤发生。我们还发现，编码围产期肌球蛋白的MYH8基因的突变导致了一种NC变异，在这种变异中，家族性心脏粘液瘤、斑点状皮肤色素沉着和内分泌病发生在肢体痉挛的背景下。PRKAR1A和MYH8可能相交或协同促进心脏发育和肿瘤发生的途径仍有待建立。我们假设MYH8和PRKAR1A基因在肿瘤发生的分子和细胞生物学途径的不同阶段起作用。MYH8突变可能促进胚胎细胞作为肿瘤前体细胞持续到成年，而PRKAR1A突变改变成年细胞内信号转导环境，刺激这些前体细胞的致瘤扩张。因此，我们建议：[1]确定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增加PKA活性介导，以及[3]确定突变导致人类数控的新基因。为了实现这些目标，我们将使用基因工程鸡和小鼠模型来确定prkar1a、Myh8和其他遗传修饰物如何调控肌肉发生、心脏发育和肿瘤发生。此外，我们将研究这些基因在肌成纤维细胞群体中的作用，以确定这一谱系对NC的贡献。最后，我们还将发现新的数控疾病基因，以确定与PRKAR1A和MYH8交叉的其他致病机制。我们的研究不仅将突出心脏粘液瘤和其他计算机控制肿瘤治疗的潜在靶点，还将阐明调节细胞分化和生长的基本机制，这些机制将促进各种常见心肌病的改进治疗。

DESCRIPTION (provided by applicant): 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 prkar1a +/- 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 prkar1a, 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.