Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• The Ornithine decarboxylase 1 (ODC1) gene is implicated in various diseases, including rare developmental disorders and neurological conditions such as schizophrenia and epilepsy.
• Gain-of-function variants in ODC1 are associated with developmental delay, alopecia, macrocephaly, and brain anomalies.
• Growing evidence suggests ODC1's role in neurological functions, necessitating a comprehensive analysis of its genotype-phenotype associations.

Purpose of the Study:

• To systematically analyze ODC1 genotype-to-phenotype associations.
• To investigate the role of ODC1 in neural progenitor cell proliferation and neurodevelopmental disorders.

Main Methods:

• Analysis of ODC1 variants from multiple databases (ClinVar, Geno2MP, TOPMed, gnomAD, COSMIC).
• Examination of expression quantitative trait loci (eQTLs) for non-coding variants regulating ODC1.
• RNA-sequencing (RNA-Seq) analysis during fetal brain development and in cerebral organoids.

Main Results:

• Identified a loss-of-function variant (ODC G84R) linked to intellectual disability and seizures, prevalent in South Asian populations.
• Discovered functionally annotated, non-coding ODC1 variants associated with psychiatric and neurological phenotypes via eQTLs.
• Demonstrated ODC1 expression correlates with neural progenitor cell proliferation, suggesting gain-of-function variants cause over-proliferation and loss-of-function variants cause depletion.

Conclusions:

• ODC1 is a bona fide neurodevelopmental disorder gene, with its expression linked to early neural progenitor proliferation.
• The study establishes a connection between ODC1 function, polyamine metabolism, and brain development.
• Findings highlight ODC1 as a potential target for understanding and treating neurodevelopmental disorders.