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Shifting landscapes of human MTHFR missense-variant effects
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 inte...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322931/ https://www.ncbi.nlm.nih.gov/pubmed/34214447 http://dx.doi.org/10.1016/j.ajhg.2021.05.009 |
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author | Weile, Jochen Kishore, Nishka Sun, Song Maaieh, Ranim Verby, Marta Li, Roujia Fotiadou, Iosifina Kitaygorodsky, Julia Wu, Yingzhou Holenstein, Alexander Bürer, Céline Blomgren, Linnea Yang, Shan Nussbaum, Robert Rozen, Rima Watkins, David Gebbia, Marinella Kozich, Viktor Garton, Michael Froese, D. Sean Roth, Frederick P. |
author_facet | Weile, Jochen Kishore, Nishka Sun, Song Maaieh, Ranim Verby, Marta Li, Roujia Fotiadou, Iosifina Kitaygorodsky, Julia Wu, Yingzhou Holenstein, Alexander Bürer, Céline Blomgren, Linnea Yang, Shan Nussbaum, Robert Rozen, Rima Watkins, David Gebbia, Marinella Kozich, Viktor Garton, Michael Froese, D. Sean Roth, Frederick P. |
author_sort | Weile, Jochen |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8322931 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-83229312021-07-31 Shifting landscapes of human MTHFR missense-variant effects Weile, Jochen Kishore, Nishka Sun, Song Maaieh, Ranim Verby, Marta Li, Roujia Fotiadou, Iosifina Kitaygorodsky, Julia Wu, Yingzhou Holenstein, Alexander Bürer, Céline Blomgren, Linnea Yang, Shan Nussbaum, Robert Rozen, Rima Watkins, David Gebbia, Marinella Kozich, Viktor Garton, Michael Froese, D. Sean Roth, Frederick P. Am J Hum Genet Article 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. Elsevier 2021-07-01 2021-07-01 /pmc/articles/PMC8322931/ /pubmed/34214447 http://dx.doi.org/10.1016/j.ajhg.2021.05.009 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Weile, Jochen Kishore, Nishka Sun, Song Maaieh, Ranim Verby, Marta Li, Roujia Fotiadou, Iosifina Kitaygorodsky, Julia Wu, Yingzhou Holenstein, Alexander Bürer, Céline Blomgren, Linnea Yang, Shan Nussbaum, Robert Rozen, Rima Watkins, David Gebbia, Marinella Kozich, Viktor Garton, Michael Froese, D. Sean Roth, Frederick P. Shifting landscapes of human MTHFR missense-variant effects |
title | Shifting landscapes of human MTHFR missense-variant effects |
title_full | Shifting landscapes of human MTHFR missense-variant effects |
title_fullStr | Shifting landscapes of human MTHFR missense-variant effects |
title_full_unstemmed | Shifting landscapes of human MTHFR missense-variant effects |
title_short | Shifting landscapes of human MTHFR missense-variant effects |
title_sort | shifting landscapes of human mthfr missense-variant effects |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322931/ https://www.ncbi.nlm.nih.gov/pubmed/34214447 http://dx.doi.org/10.1016/j.ajhg.2021.05.009 |
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