ArticleMolecular genetics & genomic medicine2020
Noonan syndrome-associated biallelic LZTR1 mutations cause cardiac hypertrophy and vascular malformations in zebrafish.
Article in Molecular genetics & genomic medicine, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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6 citing papers in PubMed, 23 citations in OpenAlex.
- Assessment of the FRET-based Teen sensor to monitor ERK activation changes preceding morphological defects in a RASopathy zebrafish model and phenotypic rescue by MEK inhibitor.Molecular medicine (Cambridge, Mass.) · 2024Article
- The molecular genetics of RASopathies: An update on novel disease genes and new disorders.American journal of medical genetics. Part C, Seminars in medical genetics · 2022Review
- The RASopathies: from pathogenetics to therapeutics.Disease models & mechanisms · 2022Review
- Zebrafish Heart Failure Models.Frontiers in cell and developmental biology · 2021Review
- Review
- Noonan syndrome-associated biallelic LZTR1 mutations cause cardiac hypertrophy and vascular malformations in zebrafish.Molecular genetics & genomic medicine · 2020Article
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10 authors at 4 institutions in 1 country.
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Abstract
backgroundVariants in the LZTR1 (leucine-zipper-like transcription regulator 1) gene (OMIM #600574) have been reported in recessive Noonan syndrome patients. In vivo evidence from animal models to support its causative role is lacking.
methodsBy CRISPR-Cas9 genome editing, we generated lztr1-mutated zebrafish (Danio rerio). Analyses of histopathology and downstream signaling were performed to investigate the pathogenesis of cardiac and extracardiac abnormalities in Noonan syndrome.
resultsA frameshift deletion allele was created in the zebrafish lztr1. Crosses of heterozygotes obtained homozygous lztr1 null mutants that modeled LZTR1 loss-of-function. Histological analyses of the model revealed ventricular hypertrophy, the deleterious signature of Noonan syndrome-associated cardiomyopathy. Further, assessment for extracardiac abnormalities documented multiple vascular malformations, resembling human vascular pathology caused by RAS/MAPK activation. Due to spatiotemporal regulation of LZTR1, its downstream function was not fully elucidated from western blots of adult tissue.
conclusionOur novel zebrafish model phenocopied human recessive Noonan syndrome and supported the loss-of-function mechanism of disease-causing LZTR1 variants. The discovery of vascular malformations in mutants calls for the clinical follow-up of patients to monitor for its emergence. The model will serve as a novel platform for investigating the pathophysiology linking RAS/MAPK signaling to cardiac and vascular pathology.
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