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@ARTICLE{Busley:1037157,
      author       = {Busley, Alexandra Viktoria and Gutiérrez-Gutiérrez,
                      Óscar and Hammer, Elke and Koitka, Fabian and
                      Mirzaiebadizi, Amin and Steinegger, Martin and Pape,
                      Constantin and Böhmer, Linda and Schroeder, Henning and
                      Kleinsorge, Mandy and Engler, Melanie and Cirstea, Ion
                      Cristian and Gremer, Lothar and Willbold, Dieter and
                      Altmüller, Janine and Marbach, Felix and Hasenfuss, Gerd
                      and Zimmermann, Wolfram-Hubertus and Ahmadian, Mohammad Reza
                      and Wollnik, Bernd and Cyganek, Lukas},
      title        = {{M}utation-induced {LZTR}1 polymerization provokes cardiac
                      pathology in recessive {N}oonan syndrome},
      journal      = {Cell reports},
      volume       = {43},
      number       = {7},
      issn         = {2211-1247},
      address      = {Maryland Heights, MO},
      publisher    = {Cell Press},
      reportid     = {FZJ-2025-00502},
      pages        = {114448 -},
      year         = {2024},
      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.},
      cin          = {IBI-7},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IBI-7-20200312},
      pnm          = {5241 - Molecular Information Processing in Cellular Systems
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5241},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {39003740},
      UT           = {WOS:001270335000001},
      doi          = {10.1016/j.celrep.2024.114448},
      url          = {https://juser.fz-juelich.de/record/1037157},
}