The Melody of Miscommunication in the Heart Decoding LZTR1 deficiency with a Multicellular Focus

by Jakob Fell
Doctoral thesis
Date of Examination:2024-08-13
Date of issue:2025-03-20
Advisor:Dr. Lukas Cyganek
Referee:Dr. Lukas Cyganek
Referee:Prof. Dr. Wolfram-Hubertus Zimmermann
Persistent Address: http://dx.doi.org/10.53846/goediss-11156

 

 

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Abstract

English

LZTR1 deficiency is a known cause of Noonan syndrome (NS) and is linked to early-onset and severe hypertrophic cardiomyopathy (HCM). Despite the recognized importance of paracrine communication in cardiac pathology, the specific pathomechanisms leading to HCM and cardiac fibrosis in NS remain unclear. In this study, we utilized both 2D and 3D iPSC models with LZTR1 deficiency to investigate the role of non-cardiomyocytes in the development of NS-associated HCM. Our findings reveal that autocrine and paracrine crosstalk, particularly active in the disease state, is a key driver of cardiac hypertrophy and fibrosis. We demonstrated that LZTR1 deficiency induces fibrosis-related signatures in cardiac fibroblasts and enhances cardiomyocyte hypertrophy.
Keywords: Noonan syndrome; hypertrophic cardiomyopathy; cardiac fibrosis