TY  - JOUR
AU  - Busley, Alexandra Viktoria
AU  - Gutiérrez-Gutiérrez, Óscar
AU  - Hammer, Elke
AU  - Koitka, Fabian
AU  - Mirzaiebadizi, Amin
AU  - Steinegger, Martin
AU  - Pape, Constantin
AU  - Böhmer, Linda
AU  - Schroeder, Henning
AU  - Kleinsorge, Mandy
AU  - Engler, Melanie
AU  - Cirstea, Ion Cristian
AU  - Gremer, Lothar
AU  - Willbold, Dieter
AU  - Altmüller, Janine
AU  - Marbach, Felix
AU  - Hasenfuss, Gerd
AU  - Zimmermann, Wolfram-Hubertus
AU  - Ahmadian, Mohammad Reza
AU  - Wollnik, Bernd
AU  - Cyganek, Lukas
TI  - Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome
JO  - Cell reports
VL  - 43
IS  - 7
SN  - 2211-1247
CY  - Maryland Heights, MO
PB  - Cell Press
M1  - FZJ-2025-00502
SP  - 114448 -
PY  - 2024
AB  - Noonan syndrome patients harboring causative variants in LZTR1 are particularly at risk to develop severe and early-onset hypertrophic cardiomyopathy. In this study, we investigate the mechanistic consequences of a homozygous variant LZTR1L580P by using patient-specific and CRISPR-Cas9-corrected induced pluripotent stem cell (iPSC) cardiomyocytes. Molecular, cellular, and functional phenotyping in combination with in silico prediction identify an LZTR1L580P-specific disease mechanism provoking cardiac hypertrophy. The variant is predicted to alter the binding affinity of the dimerization domains facilitating the formation of linear LZTR1 polymers. LZTR1 complex dysfunction results in the accumulation of RAS GTPases, thereby provoking global pathological changes of the proteomic landscape ultimately leading to cellular hypertrophy. Furthermore, our data show that cardiomyocyte-specific MRAS degradation is mediated by LZTR1 via non-proteasomal pathways, whereas RIT1 degradation is mediated by both LZTR1-dependent and LZTR1-independent pathways. Uni- or biallelic genetic correction of the LZTR1L580P missense variant rescues the molecular and cellular disease phenotype, providing proof of concept for CRISPR-based therapies.
LB  - PUB:(DE-HGF)16
C6  - 39003740
UR  - <Go to ISI:>//WOS:001270335000001
DO  - DOI:10.1016/j.celrep.2024.114448
UR  - https://juser.fz-juelich.de/record/1037157
ER  -