Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome

Noonan Syndrome
DOI: 10.1016/j.celrep.2024.114448 Publication Date: 2024-07-13T05:04:18Z
ABSTRACT
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 CRISPR-Cas9-corrected induced pluripotent stem cell (iPSC) cardiomyocytes. Molecular, cellular, functional phenotyping combination with silico prediction identify an LZTR1L580P-specific disease mechanism provoking cardiac hypertrophy. The is predicted alter binding affinity dimerization domains facilitating formation linear polymers. complex dysfunction results accumulation RAS GTPases, thereby global pathological changes proteomic landscape ultimately leading cellular Furthermore, our data show that cardiomyocyte-specific MRAS degradation mediated via non-proteasomal pathways, whereas RIT1 both LZTR1-dependent LZTR1-independent pathways. Uni- or biallelic genetic correction missense rescues molecular phenotype, providing proof concept for CRISPR-based therapies.
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