Molecular Genetics of Cardiac Myxomas (Carney Complex)

描述(由申请人提供)：心脏粘液瘤是最常见的心脏原发肿瘤。它们是良性肿瘤，通过栓塞、心力衰竭和体质症状导致发病率和死亡率。大约7%的心脏粘液瘤患者有家族性综合征，即Carney综合征，这是一种常染色体显性遗传病，心脏粘液瘤发生在皮肤斑点状色素沉着和内分泌疾病的背景下。这种心脏粘液瘤可以发生在所有的心腔，可以是多中心的，并且经常复发。我们确定了人类染色体17q24上的一个主要疾病位点，并表明那里的PRKAR1a(蛋白激酶A的一个亚单位)基因的突变导致了近2/3的患者出现Carney综合征。大多数PRKARLA突变导致单倍体功能不全。依赖于PRKARLA的Carney复合体的肿瘤发生似乎需要额外的体细胞突变。虽然PRKARLA杂合性缺失确实偶尔会发生，但其他尚未确定的基因(S)肯定在卡尼复合体和心脏粘液瘤的发病机制中发挥作用。要描述Carney复合体心脏肿瘤发生的机制，需要识别这些基因，并描述研究它们的实验模型。我们现在已经确定了一个新的基因座(“CAR2”)，其赔率为24,500：1，包含第二个卡尼复合病基因。此外，我们还发现Prkarla单倍体不足的小鼠表现出心房肌细胞核增大和内脏间质瘤。因此，我们建议[1]鉴定导致Carney复合体和心脏粘液瘤的CAR2基因，[2]鉴定与小鼠Prkara相互作用导致肿瘤发生的基因，以及[3]评估Carney复合体基因的体细胞突变对非家族性、孤立的人类心脏粘液瘤的贡献。我们将使用位置克隆候选策略来识别CAR2 Carney复合体疾病基因的突变。我们将研究不同的遗传背景和改变其他抑癌基因的基因剂量对小鼠Prkarla依赖型肿瘤发生的影响。这些研究将建立导致心脏和Carney复合体中其他器官肿瘤发生的分子遗传途径，并将提出常见的、非家族性心脏粘液瘤发病的候选基因。研究结果将突出心脏粘液瘤治疗的潜在靶点，以改变常见心血管疾病(如心力衰竭和缺血性心脏病)的心脏重塑。

DESCRIPTION (provided by applicant): Cardiac myxomas are the most common form of primary cardiac tumor. They are benign neoplasms that cause morbidity and mortality through embolism, heart failure, and constitutional symptoms. Approximately 7% of individuals with cardiac myxomas have a familial syndrome, Carney complex, an autosomal dominant disorder in which cardiac myxomas occur in the setting of spotty pigmentation of the skin and endocrinopathy. Such cardiac myxomas can occur in all cardiac chambers, may be multicentric, and often recur. We identified a major disease locus for on human chromosome 17q24 and showed that mutations of the PRKAR1 a (R1 a subunit of protein kinase A) gene there cause Carney complex in nearly 2/3 of patients. Most PRKARla mutations result in haploinsufficiency. PRKARla-dependent tumorigenesis in Carney complex appears to require additional somatic mutation. Although loss of PRKARla heterozygosity does occasionally occur, other as yet unidentified(s) genes must play a role in the pathogenesis of Carney complex and cardiac myxomas. Delineation of mechanisms of cardiac tumorigenesis in Carney complex requires the identification of such genes and characterization of experimental models in which to study them. We have now identified a novel locus ("CAR2") with odds of 24,500:1 that contains a second Carney complex disease gene. In addition, we have showed that prkarla haploinsufficient mice exhibit atrial myocyte karyomegaly, and visceral stromal tumors. Therefore, we propose [1] To identify the CAR2 gene that causes Carney complex and cardiac myxomas, [2] To characterize genes that interact with murine prkarl a to cause tumorigenesis, and [3] To assess the contribution of somatic mutation of Carney complex genes to nonfamilial, isolated human cardiac myxomas. We will use a positional cloning-candidate strategy to identify mutations in the CAR2 Carney complex disease gene. We will investigate the effects on murine prkarla dependent tumorigenesis of varied genetic backgrounds and altered gene dosage of other tumor suppressor genes. These studies will establish molecular genetic pathways that lead to tumorigenesis of the heart and other organs in Carney complex and will suggest candidate genes for the pathogenesis of common, nonfamilial cardiac myxomas. Findings will highlight potential targets for treatment of cardiac myxomas for modification of cardiac remodeling in common cardiovascular disorders such as heart failure and ischemic heart disease.