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Genomic analyses of glycine decarboxylase neurogenic mutations yield a large-scale prediction model for prenatal disease

Hundreds of mutations in a single gene result in rare diseases, but why mutations induce severe or attenuated states remains poorly understood. Defect in glycine decarboxylase (GLDC) causes Non-ketotic Hyperglycinemia (NKH), a neurological disease associated with elevation of plasma glycine. We unif...

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Autores principales: Farris, Joseph, Alam, Md Suhail, Rajashekara, Arpitha Mysore, Haldar, Kasturi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850488/
https://www.ncbi.nlm.nih.gov/pubmed/33524012
http://dx.doi.org/10.1371/journal.pgen.1009307
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author Farris, Joseph
Alam, Md Suhail
Rajashekara, Arpitha Mysore
Haldar, Kasturi
author_facet Farris, Joseph
Alam, Md Suhail
Rajashekara, Arpitha Mysore
Haldar, Kasturi
author_sort Farris, Joseph
collection PubMed
description Hundreds of mutations in a single gene result in rare diseases, but why mutations induce severe or attenuated states remains poorly understood. Defect in glycine decarboxylase (GLDC) causes Non-ketotic Hyperglycinemia (NKH), a neurological disease associated with elevation of plasma glycine. We unified a human multiparametric NKH mutation scale that separates severe from attenuated neurological disease with new in silico tools for murine and human genome level-analyses, gathered in vivo evidence from mice engineered with top-ranking attenuated and a highly pathogenic mutation, and integrated the data in a model of pre- and post-natal disease outcomes, relevant for over a hundred major and minor neurogenic mutations. Our findings suggest that highly severe neurogenic mutations predict fatal, prenatal disease that can be remedied by metabolic supplementation of dams, without amelioration of persistent plasma glycine. The work also provides a systems approach to identify functional consequences of mutations across hundreds of genetic diseases. Our studies provide a new framework for a large scale understanding of mutation functions and the prediction that severity of a neurogenic mutation is a direct measure of pre-natal disease in neurometabolic NKH mouse models. This framework can be extended to analyses of hundreds of monogenetic rare disorders where the underlying genes are known but understanding of the vast majority of mutations and why and how they cause disease, has yet to be realized.
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spelling pubmed-78504882021-02-09 Genomic analyses of glycine decarboxylase neurogenic mutations yield a large-scale prediction model for prenatal disease Farris, Joseph Alam, Md Suhail Rajashekara, Arpitha Mysore Haldar, Kasturi PLoS Genet Research Article Hundreds of mutations in a single gene result in rare diseases, but why mutations induce severe or attenuated states remains poorly understood. Defect in glycine decarboxylase (GLDC) causes Non-ketotic Hyperglycinemia (NKH), a neurological disease associated with elevation of plasma glycine. We unified a human multiparametric NKH mutation scale that separates severe from attenuated neurological disease with new in silico tools for murine and human genome level-analyses, gathered in vivo evidence from mice engineered with top-ranking attenuated and a highly pathogenic mutation, and integrated the data in a model of pre- and post-natal disease outcomes, relevant for over a hundred major and minor neurogenic mutations. Our findings suggest that highly severe neurogenic mutations predict fatal, prenatal disease that can be remedied by metabolic supplementation of dams, without amelioration of persistent plasma glycine. The work also provides a systems approach to identify functional consequences of mutations across hundreds of genetic diseases. Our studies provide a new framework for a large scale understanding of mutation functions and the prediction that severity of a neurogenic mutation is a direct measure of pre-natal disease in neurometabolic NKH mouse models. This framework can be extended to analyses of hundreds of monogenetic rare disorders where the underlying genes are known but understanding of the vast majority of mutations and why and how they cause disease, has yet to be realized. Public Library of Science 2021-02-01 /pmc/articles/PMC7850488/ /pubmed/33524012 http://dx.doi.org/10.1371/journal.pgen.1009307 Text en © 2021 Farris et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://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
Farris, Joseph
Alam, Md Suhail
Rajashekara, Arpitha Mysore
Haldar, Kasturi
Genomic analyses of glycine decarboxylase neurogenic mutations yield a large-scale prediction model for prenatal disease
title Genomic analyses of glycine decarboxylase neurogenic mutations yield a large-scale prediction model for prenatal disease
title_full Genomic analyses of glycine decarboxylase neurogenic mutations yield a large-scale prediction model for prenatal disease
title_fullStr Genomic analyses of glycine decarboxylase neurogenic mutations yield a large-scale prediction model for prenatal disease
title_full_unstemmed Genomic analyses of glycine decarboxylase neurogenic mutations yield a large-scale prediction model for prenatal disease
title_short Genomic analyses of glycine decarboxylase neurogenic mutations yield a large-scale prediction model for prenatal disease
title_sort genomic analyses of glycine decarboxylase neurogenic mutations yield a large-scale prediction model for prenatal disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850488/
https://www.ncbi.nlm.nih.gov/pubmed/33524012
http://dx.doi.org/10.1371/journal.pgen.1009307
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