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

Busley, A., Gutiérrez-Gutiérrez, Ó., Hammer, E., Koitka, F., Mirzaiebadizi, A., Steinegger, M., et al. (2024). Mutation-induced LZTR1 polymerization provokes cardiac pathology in recessive Noonan syndrome. Cell Reports, 43(7): 114448. doi:10.1016/j.celrep.2024.114448.

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Busley, A.V., Author
Gutiérrez-Gutiérrez, Ó., Author
Hammer, E., Author
Koitka, F., Author
Mirzaiebadizi, A., Author
Steinegger, M., Author
Pape, C., Author
Böhmer, L., Author
Schroeder, H.1, Author           
Kleinsorge, M., Author
Engler, M., Author
Cirstea, I.C., Author
Gremer, L., Author
Willbold, D., Author
Altmüller, J., Author
Marbach, F., Author
Hasenfuss, G., Author
Zimmermann, W.-H., Author
Ahmadian, M.R., Author
Wollnik, B., Author
Cyganek, L., Author more..
Affiliations:
1Research Group of NMR Signal Enhancement, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society, ou_3350277              

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 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 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.

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Language(s): eng - English
 Dates: 2024-07-23
 Publication Status: Published online
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 Rev. Type: Peer
 Identifiers: DOI: 10.1016/j.celrep.2024.114448
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Title: Cell Reports
Source Genre: Journal
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Publ. Info: Maryland Heights, MO : Cell Press
Pages: - Volume / Issue: 43 (7) Sequence Number: 114448 Start / End Page: - Identifier: ISSN: 2211-1247
CoNE: https://pure.mpg.de/cone/journals/resource/2211-1247