Molecular Genetics of Cardiac Myxomas (Carney Complex)

描述（申请人提供）：心脏黏液瘤是最常见的原发性心脏肿瘤。它们是良性肿瘤，可通过栓塞、心力衰竭和体质症状引起发病率和死亡率。大约7%的心脏黏液瘤患者患有家族性综合征卡尼综合征，这是一种常染色体显性遗传病，心脏黏液瘤发生在皮肤斑点性色素沉着和内分泌病变的背景下。这种心脏黏液瘤可发生在所有心室，可能是多中心的，并且经常复发。我们在人类染色体17q24上发现了一个主要的疾病位点，并发现prkar1a （R1是蛋白激酶a的亚基）基因突变导致近2/3的患者出现卡尼复合体。大多数PRKARla突变导致单倍不足。卡尼复合体中依赖prkarla的肿瘤发生似乎需要额外的体细胞突变。虽然偶尔会发生PRKARla杂合性缺失，但其他尚未确定的基因一定在卡尼复合体和心脏黏液瘤的发病机制中发挥作用。卡尼复合体心脏肿瘤发生机制的描述需要识别这些基因和表征实验模型来研究它们。我们现在已经确定了一个新的位点（“CAR2”），其几率为24,500:1，包含第二个卡尼复合体病基因。此外，我们发现prkarla单倍体不足的小鼠表现出心房肌细胞核肿大和内脏间质肿瘤。因此，我们提出[1]来鉴定导致Carney复合体和心脏黏液瘤的CAR2基因，[2]来鉴定与小鼠prkarl a相互作用导致肿瘤发生的基因，[3]来评估Carney复合体基因体细胞突变对非家族性分离的人类心脏黏液瘤的贡献。我们将使用位置克隆候选策略来鉴定CAR2卡尼复合体病基因的突变。我们将研究不同遗传背景和其他肿瘤抑制基因剂量对小鼠prkarla依赖性肿瘤发生的影响。这些研究将建立导致卡尼复合物中心脏和其他器官肿瘤发生的分子遗传途径，并将为常见的非家族性心脏黏液瘤的发病机制提供候选基因。研究结果将突出心脏黏液瘤治疗的潜在靶点，以改变心力衰竭和缺血性心脏病等常见心血管疾病的心脏重塑。

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.