MOLECULAR GENETICS OF CARDIAC MYXOMAS (CARNEY COMPLEX)

心血管疾病通常是多系统疾病的主要异常。 心内肿瘤，包括心房粘液瘤，是中风和心力衰竭的重要原因，并可能表现为遗传性全身性疾病。 卡尼综合征是一种常染色体显性遗传综合征，其中心内粘液瘤发生于皮肤色素沉着过度和雀斑样痣沿着较少见的心外粘液瘤以及内分泌病。 对遗传性疾病（如Carney综合征）的研究对疾病的病理生理学和正常生理学都有重要的意义。 分子遗传学技术可用于研究Carney复合体对运动功能的影响，以确定该综合征的突变致病基因。 我们的初步研究表明了这种综合征的遗传异质性，现在已经确定了一个新的13 cM基因座的长臂上的17号染色体，与6万亿：1的几率，包含卡尼复合体疾病基因在至少四个家庭。 在本申请中，我们建议确定染色体17 q上的Carney综合征基因和该基因中导致心内粘液瘤的突变。 新的微卫星和单倍型分析将用于完善l7q Carney复合基因座（CAR）遗传图谱，并组装该地区的基因组克隆重叠群。 此外，培养的粘液瘤肿瘤细胞的杂合性丢失分析将用于进一步减少含有CAR的遗传和物理间隔。 将通过建立CAR基因座的YAC和其他大插入基因组克隆重叠群来进行间隔的物理作图。 将测定已知基因，以通过基因组克隆重叠群的PCR和Southern印迹分析确定它们是否映射到CAR基因座。 通过外显子捕获和cDNA选择研究分离CAR基因座处的新转录物。 候选基因和转录本映射到这个位点，然后将评估突变，以确定卡尼复合体疾病基因。 Carney复合体基因及其相关突变的结构分析将促进肿瘤转化机制以及心脏和其他组织正常生长稳态的新概念。 增加对心脏细胞生长调节的理解将改善心内粘液瘤的诊断和治疗，也将提出新的方法来刺激心脏重塑，有助于肌病和缺血性心脏的管理。

Cardiovascular disorders often are the primary abnormalities in multisystem disease. Intracardiac tumors, including atrial myxomas, are significant causes of stroke and heart failure and may present as heritable systemic disorders. The Carney complex is an autosomal dominant syndrome in which intracardiac myxomas, arise in the setting of cutaneous hyperpigmentaton and lentiginosis along with less common extracardiac myxomas as well as endocrinopathy. Investigation of genetic diseases, such as Carney complex, yields important insights into disease pathophysiology as well as normal physiology. Molecular genetic techniques can be used to study kindreds affected by Carney complex in order to identify the mutated disease gene in this syndrome. Our preliminary investigation demonstrated genetic heterogeneity of this syndrome and now has defined a novel 13 cM locus on the long arm of chromosome 17 that, with odds of 6 trillion: 1, contains the Carney complex disease gene in at least four families. In this application, we propose to identify the Carney complex disease gene on chromosome 17q and the mutations in this gene that cause intracardiac myxomas. New microsatellites and haplotype analysis will be used to refine the l7q Carney complex locus (CAR) genetic map and to assemble a genomic clone contig of the region. In addition, loss of heterozygosity analysis of cultured myxoma tumor cells will be employed to reduce further the genetic and physical interval containing CAR. Physical mapping of the interval will be performed by establishing YAC and other large insert genomic clone contigs of the CAR locus. Known genes will be assayed to determine if they map to the CAR locus by PCR and southern blot analysis of the genomic clone contigs. Novel transcripts at the CAR locus will be isolated by exon trapping and cDNA selection studies. Candidate genes and transcripts that do map to this locus will then be evaluated for mutations to identify the Carney complex disease gene. Structural analysis of the Carney complex gene and its associated mutations will foster new concepts of mechanisms underlying neoplastic transformation as well as normal growth homeostasis in the heart and other tissues. Increased understanding of the regulation of cardiac cell growth will improve diagnosis and treatment of intracardiac myxomas and will also suggest novel approaches to stimulate cardiac remodeling that can contribute to the management of the myopathic and ischemic heart.