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California Institute for Quantitative... 1 Center for Cancer Systems Biology Dan... 1 Department of Computer Science Univer... 1 Department of Genetics Blavatnik Inst... 1 Department of Medical Biochemistry an... 1 Department of Molecular Genetics Univ... 1 Department of Molecular and Cell Biol... 1 Department of Pediatrics and Adolesce... 1 Lunenfeld Tanenbaum Research Institut... 1 The Donnelly Centre University of Tor... 1
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California Institute for Quantitative... 1 Center for Cancer Systems Biology Dan... 1 Department of Computer Science Univer... 1 Department of Genetics Blavatnik Inst... 1 Department of Medical Biochemistry an... 1 Department of Molecular Genetics Univ... 1 Department of Molecular and Cell Biol... 1 Department of Pediatrics and Adolesce... 1 Lunenfeld Tanenbaum Research Institut... 1 The Donnelly Centre University of Tor... 1
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Sun, Song
Autor Sun, Song The Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 3E1, Canada Department of Computer Science, University of Toronto, Toronto, ON, M5S 3E1, Canada Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada Department of Medical Biochemistry and Microbiology, Uppsala University, SE 75123, Uppsala, Sweden
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Weile, Jochen
Autor Weile, Jochen The Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada. jochen.weile@mail.utoronto.ca Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 3E1, Canada. jochen.weile@mail.utoronto.ca Department of Computer Science, University of Toronto, Toronto, ON, M5S 3E1, Canada. jochen.weile@mail.utoronto.ca Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada. jochen.weile@mail.utoronto.ca
- Verby, Marta
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Wu, Yingzhou
Autor Wu, Yingzhou The Donnelly Centre, University of Toronto, Toronto, ON, M5S 3E1, Canada Department of Molecular Genetics, University of Toronto, Toronto, ON, M5S 3E1, Canada Department of Computer Science, University of Toronto, Toronto, ON, M5S 3E1, Canada Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada
- Wang, Yang
- Cote, Atina G
- Fotiadou, Iosifina
- Kitaygorodsky, Julia
- Vidal, Marc
- Rine, Jasper
NLK
BioMedCentral
od 2009-01-01
BioMedCentral Open Access
od 2009
Directory of Open Access Journals
od 2009
Free Medical Journals
od 2009
PubMed Central
od 2009
Europe PubMed Central
od 2009
ProQuest Central
od 2015-01-01
Open Access Digital Library
od 2009-01-01
Open Access Digital Library
od 2009-01-01
Health & Medicine (ProQuest)
od 2015-01-01
ROAD: Directory of Open Access Scholarly Resources
od 2009
Springer Nature OA/Free Journals
od 2009-01-01
PubMed
32000841
DOI
10.1186/s13073-020-0711-1
Knihovny.cz E-zdroje
BACKGROUND: For the majority of rare clinical missense variants, pathogenicity status cannot currently be classified. Classical homocystinuria, characterized by elevated homocysteine in plasma and urine, is caused by variants in the cystathionine beta-synthase (CBS) gene, most of which are rare. With early detection, existing therapies are highly effective. METHODS: Damaging CBS variants can be detected based on their failure to restore growth in yeast cells lacking the yeast ortholog CYS4. This assay has only been applied reactively, after first observing a variant in patients. Using saturation codon-mutagenesis, en masse growth selection, and sequencing, we generated a comprehensive, proactive map of CBS missense variant function. RESULTS: Our CBS variant effect map far exceeds the performance of computational predictors of disease variants. Map scores correlated strongly with both disease severity (Spearman's ϱ = 0.9) and human clinical response to vitamin B6 (ϱ = 0.93). CONCLUSIONS: We demonstrate that highly multiplexed cell-based assays can yield proactive maps of variant function and patient response to therapy, even for rare variants not previously seen in the clinic.
- MeSH
- cystathionin-beta-synthasa genetika metabolismus MeSH
- fenotyp MeSH
- genetické testování metody MeSH
- genotyp MeSH
- homocystinurie genetika MeSH
- lidé MeSH
- missense mutace * MeSH
- Saccharomyces cerevisiae - proteiny genetika MeSH
- Saccharomyces cerevisiae MeSH
- testy genetické komplementace metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
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