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LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome

Item Type:Preprint
Title:LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome
Creators Name:Busley, A.V. and Gutiérrez-Gutiérrez, O. and Hammer, E. and Steinegger, M. and Böhmer, L. and Schroeder, H. and Kleinsorge, M. and Altmüller, J. and Marbach, F. and Hasenfuss, G. and Zimmermann, W.H. and Wollnik, B. and Cyganek, L.
Abstract:Noonan syndrome patients harboring causative variants in LZTR1 are particularly at risk to develop severe and early-onset hypertrophic cardiomyopathy. However, the underling disease mechanisms of LZTR1 missense variants driving the cardiac pathology are poorly understood. Hence, therapeutic options for Noonan syndrome patients are limited. In this study, we investigated the mechanistic consequences of a novel homozygous causative variant LZTR1L580P by using patient-specific and CRISPR/Cas9-corrected iPSC-cardiomyocytes. Molecular, cellular, and functional phenotyping in combination with in silico prediction of protein complexes uncovered a unique LZTR1L580P-specific disease mechanism provoking the cardiac hypertrophy. The homozygous variant was predicted to alter the binding affinity of the dimerization domains facilitating the formation of linear LZTR1 polymer chains. The altered polymerization resulted in dysfunction of the LZTR1-cullin 3 ubiquitin ligase complexes and subsequently, in accumulation of RAS GTPases, thereby provoking global pathological changes of the proteomic landscape ultimately leading to cellular hypertrophy. Importantly, uni- or biallelic genetic correction of the LZTR1L580P missense variant rescued the molecular and cellular disease-associated phenotype, providing proof-of-concept for CRISPR-based gene therapies.
Keywords:Cardiomyocytes, Hypertrophic Cardiomyopathy, iPSCs, LZTR1, Noonan Syndrome
Publisher:Cold Spring Harbor Laboratory Press
Article Number:2023.01.10.523203
Date:10 January 2023
Official Publication:https://doi.org/10.1101/2023.01.10.523203

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