Noonan syndrome‐associated biallelic LZTR1 mutations cause cardiac hypertrophy and vascular malformations in zebrafish
Abstract Background Variants 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. Methods By CRISPR‐Cas9 genome editing, we generated lz...
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| Format: | Article |
| Language: | English |
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Wiley
2020-03-01
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| Series: | Molecular Genetics & Genomic Medicine |
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| Online Access: | https://doi.org/10.1002/mgg3.1107 |
| _version_ | 1797301075413303296 |
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| author | Yu Nakagama Norihiko Takeda Seishi Ogawa Hiroyuki Takeda Yoshiyuki Furutani Toshio Nakanishi Tatsuyuki Sato Yoichiro Hirata Akira Oka Ryo Inuzuka |
| author_facet | Yu Nakagama Norihiko Takeda Seishi Ogawa Hiroyuki Takeda Yoshiyuki Furutani Toshio Nakanishi Tatsuyuki Sato Yoichiro Hirata Akira Oka Ryo Inuzuka |
| author_sort | Yu Nakagama |
| collection | DOAJ |
| description | Abstract Background Variants 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. Methods By 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. Results A 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. Conclusion Our 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. |
| first_indexed | 2024-03-07T23:17:12Z |
| format | Article |
| id | doaj.art-a35ab36eda294c3c9d21f00b20f0a5de |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-03-07T23:17:12Z |
| publishDate | 2020-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-a35ab36eda294c3c9d21f00b20f0a5de2024-02-21T10:43:38ZengWileyMolecular Genetics & Genomic Medicine2324-92692020-03-0183n/an/a10.1002/mgg3.1107Noonan syndrome‐associated biallelic LZTR1 mutations cause cardiac hypertrophy and vascular malformations in zebrafishYu Nakagama0Norihiko Takeda1Seishi Ogawa2Hiroyuki Takeda3Yoshiyuki Furutani4Toshio Nakanishi5Tatsuyuki Sato6Yoichiro Hirata7Akira Oka8Ryo Inuzuka9Department of Pediatrics Graduate School of Medicine The University of Tokyo Tokyo JapanDepartment of Cardiovascular Medicine Graduate School of Medicine The University of Tokyo Tokyo JapanDepartment of Pathology and Tumor Biology Graduate School of Medicine Kyoto University Kyoto JapanDepartment of Biological Sciences Graduate School of Science The University of Tokyo Tokyo JapanDepartment of Pediatric Cardiology and Adult Congenital Cardiology Tokyo Women's Medical University Tokyo JapanDepartment of Pediatric Cardiology and Adult Congenital Cardiology Tokyo Women's Medical University Tokyo JapanDepartment of Cardiovascular Medicine Graduate School of Medicine The University of Tokyo Tokyo JapanDepartment of Pediatrics Graduate School of Medicine The University of Tokyo Tokyo JapanDepartment of Pediatrics Graduate School of Medicine The University of Tokyo Tokyo JapanDepartment of Pediatrics Graduate School of Medicine The University of Tokyo Tokyo JapanAbstract Background Variants 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. Methods By 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. Results A 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. Conclusion Our 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.https://doi.org/10.1002/mgg3.1107hypertrophic cardiomyopathyLZTR1Noonan syndromeRAS/MAPK syndromevascular malformation |
| spellingShingle | Yu Nakagama Norihiko Takeda Seishi Ogawa Hiroyuki Takeda Yoshiyuki Furutani Toshio Nakanishi Tatsuyuki Sato Yoichiro Hirata Akira Oka Ryo Inuzuka Noonan syndrome‐associated biallelic LZTR1 mutations cause cardiac hypertrophy and vascular malformations in zebrafish Molecular Genetics & Genomic Medicine hypertrophic cardiomyopathy LZTR1 Noonan syndrome RAS/MAPK syndrome vascular malformation |
| title | Noonan syndrome‐associated biallelic LZTR1 mutations cause cardiac hypertrophy and vascular malformations in zebrafish |
| title_full | Noonan syndrome‐associated biallelic LZTR1 mutations cause cardiac hypertrophy and vascular malformations in zebrafish |
| title_fullStr | Noonan syndrome‐associated biallelic LZTR1 mutations cause cardiac hypertrophy and vascular malformations in zebrafish |
| title_full_unstemmed | Noonan syndrome‐associated biallelic LZTR1 mutations cause cardiac hypertrophy and vascular malformations in zebrafish |
| title_short | Noonan syndrome‐associated biallelic LZTR1 mutations cause cardiac hypertrophy and vascular malformations in zebrafish |
| title_sort | noonan syndrome associated biallelic lztr1 mutations cause cardiac hypertrophy and vascular malformations in zebrafish |
| topic | hypertrophic cardiomyopathy LZTR1 Noonan syndrome RAS/MAPK syndrome vascular malformation |
| url | https://doi.org/10.1002/mgg3.1107 |
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