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Article

Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development

1
Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI 49503, USA
2
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA
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Center for Research in Autism, Intellectual, and Other Neurodevelopmental Disabilities, Michigan State University, East Lansing, MI 48824, USA
4
Spectrum Health Medical Genetics, Grand Rapids, MI 49503, USA
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Neuroscience Program, Michigan State University, East Lansing, MI 48824, USA
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Pediatric Intensive Care Unit, Helen DeVos Children’s Hospital, Grand Rapids, MI 49503, USA
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Office of Research, Spectrum Health, Grand Rapids, MI 49503, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Eric Pasmant
Genes 2021, 12(4), 470; https://doi.org/10.3390/genes12040470
Received: 21 February 2021 / Revised: 15 March 2021 / Accepted: 22 March 2021 / Published: 25 March 2021
(This article belongs to the Special Issue Genetics of Rare Disease)
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. View Full-Text
Keywords: neural development; polyamine; ornithine decarboxylase; rs138359527 (NP_002530.1:p.Gly84Arg); variant data integration neural development; polyamine; ornithine decarboxylase; rs138359527 (NP_002530.1:p.Gly84Arg); variant data integration
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MDPI and ACS Style

Prokop, J.W.; Bupp, C.P.; Frisch, A.; Bilinovich, S.M.; Campbell, D.B.; Vogt, D.; Schultz, C.R.; Uhl, K.L.; VanSickle, E.; Rajasekaran, S.; Bachmann, A.S. Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development. Genes 2021, 12, 470. https://doi.org/10.3390/genes12040470

AMA Style

Prokop JW, Bupp CP, Frisch A, Bilinovich SM, Campbell DB, Vogt D, Schultz CR, Uhl KL, VanSickle E, Rajasekaran S, Bachmann AS. Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development. Genes. 2021; 12(4):470. https://doi.org/10.3390/genes12040470

Chicago/Turabian Style

Prokop, Jeremy W., Caleb P. Bupp, Austin Frisch, Stephanie M. Bilinovich, Daniel B. Campbell, Daniel Vogt, Chad R. Schultz, Katie L. Uhl, Elizabeth VanSickle, Surender Rajasekaran, and André S. Bachmann. 2021. "Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development" Genes 12, no. 4: 470. https://doi.org/10.3390/genes12040470

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