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Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development

Ornithine decarboxylase 1 (ODC1 gene) has been linked through gain-of-function variants to a rare disease featuring developmental delay, alopecia, macrocephaly, and structural brain anomalies. ODC1 has been linked to additional diseases like cancer, with growing evidence for neurological contributio...

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Autores principales: Prokop, Jeremy W., Bupp, Caleb P., Frisch, Austin, Bilinovich, Stephanie M., Campbell, Daniel B., Vogt, Daniel, Schultz, Chad R., Uhl, Katie L., VanSickle, Elizabeth, Rajasekaran, Surender, Bachmann, André S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064465/
https://www.ncbi.nlm.nih.gov/pubmed/33806076
http://dx.doi.org/10.3390/genes12040470
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author Prokop, Jeremy W.
Bupp, Caleb P.
Frisch, Austin
Bilinovich, Stephanie M.
Campbell, Daniel B.
Vogt, Daniel
Schultz, Chad R.
Uhl, Katie L.
VanSickle, Elizabeth
Rajasekaran, Surender
Bachmann, André S.
author_facet Prokop, Jeremy W.
Bupp, Caleb P.
Frisch, Austin
Bilinovich, Stephanie M.
Campbell, Daniel B.
Vogt, Daniel
Schultz, Chad R.
Uhl, Katie L.
VanSickle, Elizabeth
Rajasekaran, Surender
Bachmann, André S.
author_sort Prokop, Jeremy W.
collection PubMed
description Ornithine decarboxylase 1 (ODC1 gene) has been linked through gain-of-function variants to a rare disease featuring developmental delay, alopecia, macrocephaly, and structural brain anomalies. ODC1 has been linked to additional diseases like cancer, with growing evidence for neurological contributions to schizophrenia, mood disorders, anxiety, epilepsy, learning, and suicidal behavior. The evidence of ODC1 connection to neural disorders highlights the need for a systematic analysis of ODC1 genotype-to-phenotype associations. An analysis of variants from ClinVar, Geno2MP, TOPMed, gnomAD, and COSMIC revealed an intellectual disability and seizure connected loss-of-function variant, ODC G84R (rs138359527, NC_000002.12:g.10444500C > T). The missense variant is found in ~1% of South Asian individuals and results in 2.5-fold decrease in enzyme function. Expression quantitative trait loci (eQTLs) reveal multiple functionally annotated, non-coding variants regulating ODC1 that associate with psychiatric/neurological phenotypes. Further dissection of RNA-Seq during fetal brain development and within cerebral organoids showed an association of ODC1 expression with cell proliferation of neural progenitor cells, suggesting gain-of-function variants with neural over-proliferation and loss-of-function variants with neural depletion. The linkage from the expression data of ODC1 in early neural progenitor proliferation to phenotypes of neurodevelopmental delay and to the connection of polyamine metabolites in brain function establish ODC1 as a bona fide neurodevelopmental disorder gene.
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spelling pubmed-80644652021-04-24 Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development Prokop, Jeremy W. Bupp, Caleb P. Frisch, Austin Bilinovich, Stephanie M. Campbell, Daniel B. Vogt, Daniel Schultz, Chad R. Uhl, Katie L. VanSickle, Elizabeth Rajasekaran, Surender Bachmann, André S. Genes (Basel) Article Ornithine decarboxylase 1 (ODC1 gene) has been linked through gain-of-function variants to a rare disease featuring developmental delay, alopecia, macrocephaly, and structural brain anomalies. ODC1 has been linked to additional diseases like cancer, with growing evidence for neurological contributions to schizophrenia, mood disorders, anxiety, epilepsy, learning, and suicidal behavior. The evidence of ODC1 connection to neural disorders highlights the need for a systematic analysis of ODC1 genotype-to-phenotype associations. An analysis of variants from ClinVar, Geno2MP, TOPMed, gnomAD, and COSMIC revealed an intellectual disability and seizure connected loss-of-function variant, ODC G84R (rs138359527, NC_000002.12:g.10444500C > T). The missense variant is found in ~1% of South Asian individuals and results in 2.5-fold decrease in enzyme function. Expression quantitative trait loci (eQTLs) reveal multiple functionally annotated, non-coding variants regulating ODC1 that associate with psychiatric/neurological phenotypes. Further dissection of RNA-Seq during fetal brain development and within cerebral organoids showed an association of ODC1 expression with cell proliferation of neural progenitor cells, suggesting gain-of-function variants with neural over-proliferation and loss-of-function variants with neural depletion. The linkage from the expression data of ODC1 in early neural progenitor proliferation to phenotypes of neurodevelopmental delay and to the connection of polyamine metabolites in brain function establish ODC1 as a bona fide neurodevelopmental disorder gene. MDPI 2021-03-25 /pmc/articles/PMC8064465/ /pubmed/33806076 http://dx.doi.org/10.3390/genes12040470 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Prokop, Jeremy W.
Bupp, Caleb P.
Frisch, Austin
Bilinovich, Stephanie M.
Campbell, Daniel B.
Vogt, Daniel
Schultz, Chad R.
Uhl, Katie L.
VanSickle, Elizabeth
Rajasekaran, Surender
Bachmann, André S.
Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development
title Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development
title_full Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development
title_fullStr Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development
title_full_unstemmed Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development
title_short Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development
title_sort emerging role of odc1 in neurodevelopmental disorders and brain development
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064465/
https://www.ncbi.nlm.nih.gov/pubmed/33806076
http://dx.doi.org/10.3390/genes12040470
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