-
Je něco špatně v tomto záznamu ?
Shifting landscapes of human MTHFR missense-variant effects
J. Weile, N. Kishore, S. Sun, R. Maaieh, M. Verby, R. Li, I. Fotiadou, J. Kitaygorodsky, Y. Wu, A. Holenstein, C. Bürer, L. Blomgren, S. Yang, R. Nussbaum, R. Rozen, D. Watkins, M. Gebbia, V. Kozich, M. Garton, DS. Froese, FP. Roth
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, Research Support, N.I.H., Extramural, práce podpořená grantem
Grantová podpora
P50 HG004233
NHGRI NIH HHS - United States
RM1 HG010461
NHGRI NIH HHS - United States
NLK
Cell Press Free Archives
od 1997-01-01 do Před 6 měsíci
Free Medical Journals
od 1949 do Před 6 měsíci
PubMed Central
od 1949 do Před 6 měsíci
Europe PubMed Central
od 1949 do Před 6 měsíci
Open Access Digital Library
od 2005-01-01
- MeSH
- diploidie MeSH
- genotyp MeSH
- genová knihovna MeSH
- lidé MeSH
- methylentetrahydrofolátreduktasa (NADPH2) nedostatek genetika fyziologie MeSH
- missense mutace * MeSH
- mutační analýza DNA MeSH
- Saccharomyces cerevisiae genetika MeSH
- substituce aminokyselin MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Most rare clinical missense variants cannot currently be classified as pathogenic or benign. Deficiency in human 5,10-methylenetetrahydrofolate reductase (MTHFR), the most common inherited disorder of folate metabolism, is caused primarily by rare missense variants. Further complicating variant interpretation, variant impacts often depend on environment. An important example of this phenomenon is the MTHFR variant p.Ala222Val (c.665C>T), which is carried by half of all humans and has a phenotypic impact that depends on dietary folate. Here we describe the results of 98,336 variant functional-impact assays, covering nearly all possible MTHFR amino acid substitutions in four folinate environments, each in the presence and absence of p.Ala222Val. The resulting atlas of MTHFR variant effects reveals many complex dependencies on both folinate and p.Ala222Val. MTHFR atlas scores can distinguish pathogenic from benign variants and, among individuals with severe MTHFR deficiency, correlate with age of disease onset. Providing a powerful tool for understanding structure-function relationships, the atlas suggests a role for a disordered loop in retaining cofactor at the active site and identifies variants that enable escape of inhibition by S-adenosylmethionine. Thus, a model based on eight MTHFR variant effect maps illustrates how shifting landscapes of environment- and genetic-background-dependent missense variation can inform our clinical, structural, and functional understanding of MTHFR deficiency.
Department of Computer Science University of Toronto Toronto ON M5S 2E4 Canada
Department of Human Genetics McGill University Montreal QC H3A 0C7 Canada
Department of Molecular Genetics University of Toronto Toronto ON M5S 3E1 Canada
Institute of Biomedical Engineering University of Toronto ON M5S 3G9 Canada
Invitae Corp San Francisco CA 94103 USA
Lunenfeld Tanenbaum Research Institute Sinai Health System Toronto ON M5G 1X5 Canada
The Donnelly Centre University of Toronto Toronto ON M5S 3E1 Canada
Citace poskytuje Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc21025417
- 003
- CZ-PrNML
- 005
- 20211026133833.0
- 007
- ta
- 008
- 211013s2021 xxu f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1016/j.ajhg.2021.05.009 $2 doi
- 035 __
- $a (PubMed)34214447
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a xxu
- 100 1_
- $a Weile, Jochen $u Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada; 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 2E4, Canada
- 245 10
- $a Shifting landscapes of human MTHFR missense-variant effects / $c J. Weile, N. Kishore, S. Sun, R. Maaieh, M. Verby, R. Li, I. Fotiadou, J. Kitaygorodsky, Y. Wu, A. Holenstein, C. Bürer, L. Blomgren, S. Yang, R. Nussbaum, R. Rozen, D. Watkins, M. Gebbia, V. Kozich, M. Garton, DS. Froese, FP. Roth
- 520 9_
- $a Most rare clinical missense variants cannot currently be classified as pathogenic or benign. Deficiency in human 5,10-methylenetetrahydrofolate reductase (MTHFR), the most common inherited disorder of folate metabolism, is caused primarily by rare missense variants. Further complicating variant interpretation, variant impacts often depend on environment. An important example of this phenomenon is the MTHFR variant p.Ala222Val (c.665C>T), which is carried by half of all humans and has a phenotypic impact that depends on dietary folate. Here we describe the results of 98,336 variant functional-impact assays, covering nearly all possible MTHFR amino acid substitutions in four folinate environments, each in the presence and absence of p.Ala222Val. The resulting atlas of MTHFR variant effects reveals many complex dependencies on both folinate and p.Ala222Val. MTHFR atlas scores can distinguish pathogenic from benign variants and, among individuals with severe MTHFR deficiency, correlate with age of disease onset. Providing a powerful tool for understanding structure-function relationships, the atlas suggests a role for a disordered loop in retaining cofactor at the active site and identifies variants that enable escape of inhibition by S-adenosylmethionine. Thus, a model based on eight MTHFR variant effect maps illustrates how shifting landscapes of environment- and genetic-background-dependent missense variation can inform our clinical, structural, and functional understanding of MTHFR deficiency.
- 650 _2
- $a substituce aminokyselin $7 D019943
- 650 _2
- $a mutační analýza DNA $7 D004252
- 650 _2
- $a diploidie $7 D004171
- 650 _2
- $a genová knihovna $7 D015723
- 650 _2
- $a genotyp $7 D005838
- 650 _2
- $a lidé $7 D006801
- 650 _2
- $a methylentetrahydrofolátreduktasa (NADPH2) $x nedostatek $x genetika $x fyziologie $7 D042965
- 650 12
- $a missense mutace $7 D020125
- 650 _2
- $a Saccharomyces cerevisiae $x genetika $7 D012441
- 655 _2
- $a časopisecké články $7 D016428
- 655 _2
- $a Research Support, N.I.H., Extramural $7 D052061
- 655 _2
- $a práce podpořená grantem $7 D013485
- 700 1_
- $a Kishore, Nishka $u Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada; The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada
- 700 1_
- $a Sun, Song $u Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada; 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 2E4, Canada
- 700 1_
- $a Maaieh, Ranim $u Institute of Biomedical Engineering, University of Toronto, ON M5S 3G9, Canada
- 700 1_
- $a Verby, Marta $u Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada; The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada
- 700 1_
- $a Li, Roujia $u Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada; 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 2E4, Canada
- 700 1_
- $a Fotiadou, Iosifina $u Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada; The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada
- 700 1_
- $a Kitaygorodsky, Julia $u Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada; The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada
- 700 1_
- $a Wu, Yingzhou $u Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada; 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 2E4, Canada
- 700 1_
- $a Holenstein, Alexander $u Division of Metabolism and Children's Research Center, University Children's Hospital Zürich, University of Zürich, CH-8032 Zurich, Switzerland
- 700 1_
- $a Bürer, Céline $u Division of Metabolism and Children's Research Center, University Children's Hospital Zürich, University of Zürich, CH-8032 Zurich, Switzerland
- 700 1_
- $a Blomgren, Linnea $u Division of Metabolism and Children's Research Center, University Children's Hospital Zürich, University of Zürich, CH-8032 Zurich, Switzerland
- 700 1_
- $a Yang, Shan $u Invitae Corp, San Francisco, CA 94103, USA
- 700 1_
- $a Nussbaum, Robert $u Invitae Corp, San Francisco, CA 94103, USA
- 700 1_
- $a Rozen, Rima $u Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada
- 700 1_
- $a Watkins, David $u Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada
- 700 1_
- $a Gebbia, Marinella $u Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada; The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada
- 700 1_
- $a Kozich, Viktor $u Department of Pediatrics and Inherited Metabolic Disorders, Charles University, First Faculty of Medicine and General University Hospital in Prague, Ke Karlovu 2, 12 08 Praha 2, Czech Republic
- 700 1_
- $a Garton, Michael $u Institute of Biomedical Engineering, University of Toronto, ON M5S 3G9, Canada
- 700 1_
- $a Froese, D Sean $u Division of Metabolism and Children's Research Center, University Children's Hospital Zürich, University of Zürich, CH-8032 Zurich, Switzerland
- 700 1_
- $a Roth, Frederick P $u Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada; 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 2E4, Canada. Electronic address: fritz.roth@utoronto.ca
- 773 0_
- $w MED00000254 $t American journal of human genetics $x 1537-6605 $g Roč. 108, č. 7 (2021), s. 1283-1300
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/34214447 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y p $z 0
- 990 __
- $a 20211013 $b ABA008
- 991 __
- $a 20211026133839 $b ABA008
- 999 __
- $a ok $b bmc $g 1714454 $s 1145924
- BAS __
- $a 3
- BAS __
- $a PreBMC
- BMC __
- $a 2021 $b 108 $c 7 $d 1283-1300 $e 20210701 $i 1537-6605 $m American journal of human genetics $n Am J Hum Genet $x MED00000254
- GRA __
- $a P50 HG004233 $p NHGRI NIH HHS $2 United States
- GRA __
- $a RM1 HG010461 $p NHGRI NIH HHS $2 United States
- LZP __
- $a Pubmed-20211013
