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Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation

Defects in hydroxymethylbilane synthase (HMBS) can cause Acute Intermittent Porphyria (AIP), an acute neurological disease. Although sequencing-based diagnosis can be definitive, ~⅓ of clinical HMBS variants are missense variants, and most clinically-reported HMBS missense variants are designated as...

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Autores principales: van Loggerenberg, Warren, Sowlati-Hashjin, Shahin, Weile, Jochen, Hamilton, Rayna, Chawla, Aditya, Gebbia, Marinella, Kishore, Nishka, Frésard, Laure, Mustajoki, Sami, Pischik, Elena, Di Pierro, Elena, Barbaro, Michela, Floderus, Ylva, Schmitt, Caroline, Gouya, Laurent, Colavin, Alexandre, Nussbaum, Robert, Friesema, Edith C. H., Kauppinen, Raili, To-Figueras, Jordi, Aarsand, Aasne K, Desnick, Robert J., Garton, Michael, Roth, Frederick P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9934555/
https://www.ncbi.nlm.nih.gov/pubmed/36798224
http://dx.doi.org/10.1101/2023.02.06.527353
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author van Loggerenberg, Warren
Sowlati-Hashjin, Shahin
Weile, Jochen
Hamilton, Rayna
Chawla, Aditya
Gebbia, Marinella
Kishore, Nishka
Frésard, Laure
Mustajoki, Sami
Pischik, Elena
Di Pierro, Elena
Barbaro, Michela
Floderus, Ylva
Schmitt, Caroline
Gouya, Laurent
Colavin, Alexandre
Nussbaum, Robert
Friesema, Edith C. H.
Kauppinen, Raili
To-Figueras, Jordi
Aarsand, Aasne K
Desnick, Robert J.
Garton, Michael
Roth, Frederick P.
author_facet van Loggerenberg, Warren
Sowlati-Hashjin, Shahin
Weile, Jochen
Hamilton, Rayna
Chawla, Aditya
Gebbia, Marinella
Kishore, Nishka
Frésard, Laure
Mustajoki, Sami
Pischik, Elena
Di Pierro, Elena
Barbaro, Michela
Floderus, Ylva
Schmitt, Caroline
Gouya, Laurent
Colavin, Alexandre
Nussbaum, Robert
Friesema, Edith C. H.
Kauppinen, Raili
To-Figueras, Jordi
Aarsand, Aasne K
Desnick, Robert J.
Garton, Michael
Roth, Frederick P.
author_sort van Loggerenberg, Warren
collection PubMed
description Defects in hydroxymethylbilane synthase (HMBS) can cause Acute Intermittent Porphyria (AIP), an acute neurological disease. Although sequencing-based diagnosis can be definitive, ~⅓ of clinical HMBS variants are missense variants, and most clinically-reported HMBS missense variants are designated as “variants of uncertain significance” (VUS). Using saturation mutagenesis, en masse selection, and sequencing, we applied a multiplexed validated assay to both the erythroid-specific and ubiquitous isoforms of HMBS, obtaining confident functional impact scores for >84% of all possible amino-acid substitutions. The resulting variant effect maps generally agreed with biochemical expectation. However, the maps showed variants at the dimerization interface to be unexpectedly well tolerated, and suggested residue roles in active site dynamics that were supported by molecular dynamics simulations. Most importantly, these HMBS variant effect maps can help discriminate pathogenic from benign variants, proactively providing evidence even for yet-to-be-observed clinical missense variants.
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spelling pubmed-99345552023-02-17 Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation van Loggerenberg, Warren Sowlati-Hashjin, Shahin Weile, Jochen Hamilton, Rayna Chawla, Aditya Gebbia, Marinella Kishore, Nishka Frésard, Laure Mustajoki, Sami Pischik, Elena Di Pierro, Elena Barbaro, Michela Floderus, Ylva Schmitt, Caroline Gouya, Laurent Colavin, Alexandre Nussbaum, Robert Friesema, Edith C. H. Kauppinen, Raili To-Figueras, Jordi Aarsand, Aasne K Desnick, Robert J. Garton, Michael Roth, Frederick P. bioRxiv Article Defects in hydroxymethylbilane synthase (HMBS) can cause Acute Intermittent Porphyria (AIP), an acute neurological disease. Although sequencing-based diagnosis can be definitive, ~⅓ of clinical HMBS variants are missense variants, and most clinically-reported HMBS missense variants are designated as “variants of uncertain significance” (VUS). Using saturation mutagenesis, en masse selection, and sequencing, we applied a multiplexed validated assay to both the erythroid-specific and ubiquitous isoforms of HMBS, obtaining confident functional impact scores for >84% of all possible amino-acid substitutions. The resulting variant effect maps generally agreed with biochemical expectation. However, the maps showed variants at the dimerization interface to be unexpectedly well tolerated, and suggested residue roles in active site dynamics that were supported by molecular dynamics simulations. Most importantly, these HMBS variant effect maps can help discriminate pathogenic from benign variants, proactively providing evidence even for yet-to-be-observed clinical missense variants. Cold Spring Harbor Laboratory 2023-02-06 /pmc/articles/PMC9934555/ /pubmed/36798224 http://dx.doi.org/10.1101/2023.02.06.527353 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
van Loggerenberg, Warren
Sowlati-Hashjin, Shahin
Weile, Jochen
Hamilton, Rayna
Chawla, Aditya
Gebbia, Marinella
Kishore, Nishka
Frésard, Laure
Mustajoki, Sami
Pischik, Elena
Di Pierro, Elena
Barbaro, Michela
Floderus, Ylva
Schmitt, Caroline
Gouya, Laurent
Colavin, Alexandre
Nussbaum, Robert
Friesema, Edith C. H.
Kauppinen, Raili
To-Figueras, Jordi
Aarsand, Aasne K
Desnick, Robert J.
Garton, Michael
Roth, Frederick P.
Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation
title Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation
title_full Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation
title_fullStr Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation
title_full_unstemmed Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation
title_short Systematically testing human HMBS missense variants to reveal mechanism and pathogenic variation
title_sort systematically testing human hmbs missense variants to reveal mechanism and pathogenic variation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9934555/
https://www.ncbi.nlm.nih.gov/pubmed/36798224
http://dx.doi.org/10.1101/2023.02.06.527353
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