Shifting landscapes of human MTHFR missense-variant effects
| Autor: | Céline Bürer, Viktor Kozich, D. Sean Froese, Jochen Weile, Song Sun, Marinella Gebbia, Nishka Kishore, Robert L. Nussbaum, Iosifina Fotiadou, David Watkins, Alexander Holenstein, Ranim Maaieh, Roujia Li, Michael Garton, Rima Rozen, Linnea Blomgren, Shan Yang, Frederick P. Roth, Yingzhou Wu, Marta Verby, Julia Kitaygorodsky |
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| Rok vydání: | 2021 |
| Předmět: |
Genotype
Methylenetetrahydrofolate reductase deficiency Folate Metabolism DNA Mutational Analysis Mutation Missense Homocystinuria Saccharomyces cerevisiae folate Article homocystinuria 03 medical and health sciences 0302 clinical medicine deep mutational scanning Dietary folate Genetics medicine Humans Missense mutation variant effect mapping Methylenetetrahydrofolate Reductase (NADPH2) Genetics (clinical) Gene Library 030304 developmental biology mthfr 0303 health sciences biology clinical variant interpretation cystathionine beta synthase medicine.disease Diploidy methylenetetrahydrofolate reductase Cystathionine beta synthase Phenotype molecular dynamics digestive system diseases Amino Acid Substitution Methylenetetrahydrofolate reductase gene- environment interaction biology.protein 030217 neurology & neurosurgery |
| Zdroj: | American Journal of Human Genetics |
| ISSN: | 0002-9297 |
| DOI: | 10.1016/j.ajhg.2021.05.009 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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