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Understanding molecular mechanisms and predicting phenotypic effects of pathogenic tubulin mutations

Cells rely heavily on microtubules for several processes, including cell division and molecular trafficking. Mutations in the different tubulin-α and -β proteins that comprise microtubules have been associated with various diseases and are often dominant, sporadic and congenital. While the earliest...

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Autores principales: Attard, Thomas J., Welburn, Julie P. I., Marsh, Joseph A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9581425/
https://www.ncbi.nlm.nih.gov/pubmed/36206299
http://dx.doi.org/10.1371/journal.pcbi.1010611
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author Attard, Thomas J.
Welburn, Julie P. I.
Marsh, Joseph A.
author_facet Attard, Thomas J.
Welburn, Julie P. I.
Marsh, Joseph A.
author_sort Attard, Thomas J.
collection PubMed
description Cells rely heavily on microtubules for several processes, including cell division and molecular trafficking. Mutations in the different tubulin-α and -β proteins that comprise microtubules have been associated with various diseases and are often dominant, sporadic and congenital. While the earliest reported tubulin mutations affect neurodevelopment, mutations are also associated with other disorders such as bleeding disorders and infertility. We performed a systematic survey of tubulin mutations across all isotypes in order to improve our understanding of how they cause disease, and increase our ability to predict their phenotypic effects. Both protein structural analyses and computational variant effect predictors were very limited in their utility for differentiating between pathogenic and benign mutations. This was even worse for those genes associated with non-neurodevelopmental disorders. We selected tubulin-α and -β disease mutations that were most poorly predicted for experimental characterisation. These mutants co-localise to the mitotic spindle in HeLa cells, suggesting they may exert dominant-negative effects by altering microtubule properties. Our results show that tubulin mutations represent a blind spot for current computational approaches, being much more poorly predicted than mutations in most human disease genes. We suggest that this is likely due to their strong association with dominant-negative and gain-of-function mechanisms.
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spelling pubmed-95814252022-10-20 Understanding molecular mechanisms and predicting phenotypic effects of pathogenic tubulin mutations Attard, Thomas J. Welburn, Julie P. I. Marsh, Joseph A. PLoS Comput Biol Research Article Cells rely heavily on microtubules for several processes, including cell division and molecular trafficking. Mutations in the different tubulin-α and -β proteins that comprise microtubules have been associated with various diseases and are often dominant, sporadic and congenital. While the earliest reported tubulin mutations affect neurodevelopment, mutations are also associated with other disorders such as bleeding disorders and infertility. We performed a systematic survey of tubulin mutations across all isotypes in order to improve our understanding of how they cause disease, and increase our ability to predict their phenotypic effects. Both protein structural analyses and computational variant effect predictors were very limited in their utility for differentiating between pathogenic and benign mutations. This was even worse for those genes associated with non-neurodevelopmental disorders. We selected tubulin-α and -β disease mutations that were most poorly predicted for experimental characterisation. These mutants co-localise to the mitotic spindle in HeLa cells, suggesting they may exert dominant-negative effects by altering microtubule properties. Our results show that tubulin mutations represent a blind spot for current computational approaches, being much more poorly predicted than mutations in most human disease genes. We suggest that this is likely due to their strong association with dominant-negative and gain-of-function mechanisms. Public Library of Science 2022-10-07 /pmc/articles/PMC9581425/ /pubmed/36206299 http://dx.doi.org/10.1371/journal.pcbi.1010611 Text en © 2022 Attard et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Attard, Thomas J.
Welburn, Julie P. I.
Marsh, Joseph A.
Understanding molecular mechanisms and predicting phenotypic effects of pathogenic tubulin mutations
title Understanding molecular mechanisms and predicting phenotypic effects of pathogenic tubulin mutations
title_full Understanding molecular mechanisms and predicting phenotypic effects of pathogenic tubulin mutations
title_fullStr Understanding molecular mechanisms and predicting phenotypic effects of pathogenic tubulin mutations
title_full_unstemmed Understanding molecular mechanisms and predicting phenotypic effects of pathogenic tubulin mutations
title_short Understanding molecular mechanisms and predicting phenotypic effects of pathogenic tubulin mutations
title_sort understanding molecular mechanisms and predicting phenotypic effects of pathogenic tubulin mutations
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9581425/
https://www.ncbi.nlm.nih.gov/pubmed/36206299
http://dx.doi.org/10.1371/journal.pcbi.1010611
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