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Noonan syndrome patients harboring causative variants inLZTR1are particularly at risk to develop severe and early-onset hypertrophic cardiomyopathy. However, the underling disease mechanisms ofLZTR1missense 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 variantLZTR1L580Pby using patient-specific and CRISPR/Cas9-corrected iPSC-cardiomyocytes. Molecular, cellular, and functional phenotyping in combination within silicoprediction of protein complexes uncovered a uniqueLZTR1L580P-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 theLZTR1L580Pmissense variant rescued the molecular and cellular disease-associated phenotype, providing proof-of-concept for CRISPR-based gene therapies. |
