title: Novel PDE10A transcript diversity in the human striatum: Insights into gene complexity, conservation and regulation.
abstract: PDE10A is a cAMP/cGMP phosphodiesterase important in signal transduction within medium spiny neurons of the human striatum. This gene region has been associated with bipolar disorder via case-control and linkage studies. The three most studied human PDE10A isoforms differ in both their N-termini and trafficking within the cell with PDE10A2 found predominantly at the plasma membrane and PDE10A1 and PDE10A19 remaining primarily within the cytosol. RNA-sequencing and 5' RLM-RACE studies of the human putamen and caudate nucleus revealed 16 new exons and 12 novel transcripts of PDE10A, 3 of which are predicted to produce proteins with unique N-termini. The novel first exons of these transcripts are highly conserved in non-human primate species and are rarely found in other mammals. One hundred and eight previously classified intronic SNPs were found within the novel PDE10A exons of which 78% were classified as rare variants. Since most of the rare variants localize to 5' UTR regions, they may influence PDE10A transcription, translation, or mRNA stability. Dysregulation of cAMP signaling has been proposed as a cause of bipolar disorder and PDE10A inhibitors have been investigated as potential therapeutics for schizophrenia. Understanding the mechanisms contributing to PDE10A expression in the human striatum may provide evidence linking this gene to the phenotypes observed in neuropsychiatric disorders.
authors.affiliation: Department of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL 33410, USA.
authors.forename: Courtney M
authors.initials: CM
authors.lastname: MacMullen
authors.affiliation: Informatics Core, The Scripps Research Institute Florida, Jupiter, FL 33410, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Fallahi
authors.affiliation: Department of Neuroscience, The Scripps Research Institute Florida, Jupiter, FL 33410, USA. Electronic address: rdavis@scripps.edu.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Davis
mesh_terms: D000368:Aged; D000818:Animals; D001714:Bipolar Disorder / Q000235:genetics; D002421:Caudate Nucleus / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D021141:Nucleic Acid Amplification Techniques; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011699:Putamen / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics
chemical_list: C119843:PDE10A protein, human; D010727:Phosphoric Diester Hydrolases
keywords: Bipolar disorder; Evolution; Gene regulation; PDE10A; RNA-sequencing; Rare variants; Schizophrenia