Molecular Pathogenesis of the Cardiomyogenic Defects in LEOPARD Syndrome

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DESCRIPTION (provided by applicant): 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 approximately 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. (End of Abstract)