Molecular Genetics of Carney Complex

描述（由申请方提供）：卡尼综合征（CNC）是一种常染色体显性遗传疾病，其中心脏粘液瘤（最常见的原发性心脏肿瘤）发生在皮肤斑点状色素沉着、心外粘液瘤、罕见的非粘液瘤性肿瘤和内分泌病的背景下。我们已经证明，编码cAMP依赖性蛋白激酶A的R1 a调节亚基的PRKAR 1A基因的单倍不足突变导致约2/3的CNC。此外，我们的prkar 1a +/-敲除小鼠复制了CNC的几个方面，包括男性不育和肿瘤发生。这两种小鼠表型都是通过基因消融Ca PKA催化亚基来拯救的，并且类似的遗传修饰剂可能会改变人类肿瘤发生。我们还发现，编码围产期肌球蛋白的MYH 8基因突变导致CNC变异，其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挛缩的情况下。PRKAR 1A和MYH 8可以交叉或协同作用以促进心脏发育和肿瘤发生的途径仍有待建立。我们假设MYH 8和PRKAR 1A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。MYH 8突变可促进胚胎细胞持续到成年期，这些胚胎细胞可充当肿瘤祖细胞，而PRKAR 1A突变改变成年细胞内信号转导环境以刺激这些祖细胞的致瘤性扩增。因此，我们建议：[1]确定心脏发生和肿瘤发生期间围产期肌球蛋白的需求，[2]确定PRKAR 1 A依赖性肿瘤发生是否通过PKA活性增加介导，[3]鉴定突变导致人类CNC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prkar 1a，Myh 8和其他遗传修饰剂如何调节肌生成，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，以确定该谱系对CNC的贡献。最后，我们还将确定新的CNC疾病基因，以确定与PRKAR 1A和MYH 8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CNC肿瘤治疗的潜在靶点，而且还将揭示调节细胞分化和生长的基本机制，这将促进各种常见心肌病的治疗。

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.