Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development

Abstract

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.

Development of a Redox-Sensitive Spermine Prodrug for the Potential Treatment of Snyder Robinson Syndrome

“…Another phenotype from this X-linked disorder is impaired intellectual function, presumably due to reduced spermine levels in the brain. Indeed, polyamines are important for neurodevelopment because mutations in other enzymes in the polyamine pathway (ODC, DHPS, and eIF5A) have also been linked to neurodevelopmental disorders. − …”

Polyamines and Their Metabolism: From the Maintenance of Physiological Homeostasis to the Mediation of Disease

“…The strict control of polyamine levels is necessary, as imbalances in their cellular pools can have many detrimental outcomes. For example, alterations in ODC and SMS functions can cause abnormalities in physical and mental development [ 137 , 156 , 157 , 159 , 160 , 161 ]. Potential alteration in lysosomal transport of polyamines caused by mutations in ATP13A2 are also associated with a form of juvenile onset Parkinsonism [ 55 ].…”

“…The importance of ODC in the regulation of cell growth, differentiation, and function has been well established [ 134 , 135 ]. The physiological importance of ODC was further established in knock-out mice, where the homozygote ablation of its alleles was shown to be lethal and to have adverse developmental effects in heterozygote mice [ 136 , 137 ]. ODC expression and regulation is altered in response to injuries and in cancer [ 16 , 17 , 138 , 139 ].…”

“…In a single case of ODC gain of function mutation, eflornithine normalized the polyamine levels while improving alopecia and neurological symptoms [ 158 ]. A loss of function mutation of ODC (gly84Arg) was also recently described in South Asian individuals [ 137 ]. This missense variant reduces the activity of ODC by nearly 60% and is associated with psychiatric and neurological traits [ 137 ].…”

“…A loss of function mutation of ODC (gly84Arg) was also recently described in South Asian individuals [ 137 ]. This missense variant reduces the activity of ODC by nearly 60% and is associated with psychiatric and neurological traits [ 137 ].…”