Molecular Pathogenesis of the Cardiomyogenic Defects in LEOPARD Syndrome

摘要：最近，含有SH 2结构域的蛋白酪氨酸磷酸酶Shp 2突变， 与心脏病有关Shp 2被鉴定为约50%努南病例中的基因突变 综合征（NS）和所有LEOPARD综合征（LS）病例。NS和LS有几个共同的临床特征， 包括先天性心脏缺陷，因此被视为重叠综合征。但是，LS不是一个 NS的疾病变体; Shp 2中LS相关突变无催化活性，表现为显性 阴性，而NS中的Shp 2突变是催化过度活跃的。这提出了一个模型，其中LS 突变是功能丧失，NS突变是功能获得。此外，大多数LS患者发展为 肥厚型心肌病（HCM），这是LS所特有的;很少有Shp 2突变的NS患者发生 HCM。因此，中心假设是，这两种综合征之间的生化差异 疾病引起明显的心脏缺陷。本提案将定义Shp 2 LS 突变体干扰Erk/MAPK中Ras上游和/或下游的正信号事件 通路，将确定心脏中由LS异常调节的信号通路， 在心脏发生过程中需要Shp 2的发育间隔，并将产生和功能 分析LS的鼠模型。候选人：Maria Kontarovich将在以下领域接受高级培训： 心脏病学，并将进一步发展在分子和发育生物学，生物化学和小鼠的技能， 在这个奖项的指导阶段。她的赞助人本杰明·尼尔是Shp 2的专家， 小鼠遗传学她的顾问小组（乔纳森·塞德曼、杰弗里·萨菲茨、刘易斯·坎特利和詹姆斯· Chang），所有心脏发育/病理生理学和/或信号转导方面的专家， 对她的培训和职业发展有很大的帮助。从长远来看，她计划成为一名独立的 一位学术机构的研究科学家，并指导她自己的心脏发育实验室， 强调导致先天性心脏病的信号机制（及其突变）。 相关性：这项工作将进一步确定基因突变导致心脏病的机制。 疾病这些发现将通过更好地了解心脏功能和发病机制， 了解介导这些过程的基本信号机制。

SUMMARY: Recently, mutations in the SH2 domain-containing protein tyrosine phosphatase Shp2, have been implicated in cardiac disease. Shp2 was identified as the gene mutated in -50% of cases of Noonan Syndrome (NS) and all cases of LEOPARD Syndrome (LS). NS and LS share several clinical features, including congenital heart defects, and, as such, were viewed as overlap syndromes. However, LS is NOT a disease variant of NS; LS-associated mutations in Shp2 are catalytically inactive and behave as dominant negatives, whereas Shp2 mutations in NS are catalytically hyperactive. This proposes a model in which LS mutations are loss-of-function and NS mutations are gain-of-function. Moreover, most LS patients develop a hypertrophic cardiomyopathy (HCM), which is unique to LS; few NS patients with Shp2 mutations develop HCM. The central hypothesis, therefore, is that biochemical differences between these two syndromic disorders give rise to distinct cardiac defects. This proposal will define the mechanism(s) by which Shp2 LS mutants interfere with positive signaling events upstream and/or downstream of Ras in the Erk/MAPK pathway, will determine the signaling pathways that are aberrantly regulated by LS in the heart, will identify the developmental interval in which Shp2 is required during cardiogenesis, and will generate and functionally analyze a murine model of LS. CANDIDATE: Maria Kontaridis will receive advanced training in the field of cardiology and will further develop skills in molecular and developmental biology, biochemistry, and mouse genetics during the mentored phase of this award. Benjamin Neel, her sponsor, is an expert in Shp2 and mouse genetics. Her advisory panel (Drs. Jonathan Seidman, Jeffrey Saffitz, Lewis Cantley and James Chang), all experts in cardiac development/pathophysiology and/or signal transduction, will contribute substantially to her training and career development. Long-term, she plans to become an independent research scientist at an academic institution and to direct her own lab in cardiac development, with an emphasis on the signaling mechanisms (and mutations therein) that lead to congenital heart disease. RELEVANCE: This work will further define the mechanisms by which genetic mutations lead to cardiac disease. These findings will advance our knowledge of cardiac function and pathogenesis through better understanding of the fundamental signaling mechanisms that mediate these processes.