About the importance of LZTR1 for the development of cardiac hypertrophy in patients with Noonan syndrome

• Applicant: Dr. Lukas Cyganek
• Subject Area: Human Genetics ; Cardiology, Angiology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 417880571

In the recent years, studies from others and us uncovered the cellular function of LZTR1 as an adaptor for the Cullin 3 ubiquitin ligase complex with RAS proteins being its targets for degradation. LZTR1-deficiency results in accumulation of RAS proteins causing hyperactivity of the RAS-MAPK signaling commonly observed in Noonan syndrome (NS). Our data showed that the patients’ iPSC-derived cardiomyocytes (iPSC-CMs) recapitulate the hypertrophic phenotype in vitro and revealed a causal link between LZTR1 dysfunction, RAS-MAPK signaling hyperactivity, hypertrophic gene response and cellular hypertrophy. An intronic CRISPR repair was able to rescue the pathological cardiac disease phenotype and might be considered as potential therapeutic strategy for the treatment of NS-associated hypertrophic cardiomyopathy (HCM), which is the primary cause of death for these patients. A significant part of our recently published data was obtained in the framework of our currently ongoing DFG grant (project number 417880571).Although we can now benefit from first insights in the cellular function of LZTR1 and its link to the RAS-MAPK pathway, the molecular mechanisms underlying the development of HCM as a cause of LZTR1 dysfunction are not fully understood. In the renewal proposal, we aim to understand the cardiac pathology upon LZTR1 dysfunction by deeply phenotyping LZTR1-deficient iPSC-derived cardiac cell types on the molecular, (sub)cellular and functional level. First, LZTR1-deficient iPSC-CMs will be analyzed for cellular hypertrophy, proliferative capacity, apoptosis, sarcomeric organization, contractility, rhythmogenesis, energy metabolism and metabolic remodeling. Second, we will prove whether additional factors and alternative signaling pathways are involved in disease progression by analyzing the proteomic and phospho-proteomic profiles of LZTR1-deficient iPSC-CMs. Third, we aim to identify novel cardiac-specific LZTR1 interaction partners that promote the cardiac dysfunction and could serve as selective therapeutic targets. Forth, we aim to validate the importance of the localization of LZTR1 in intracellular compartments for its function. In summary, the elucidation of the pathomechanisms how LZTR1 deficiency promotes the cardiomyopathy phenotype might facilitate the identification of novel therapeutic strategies in the sense of personalized medicine.

• DFG Programme: Research Grants