Abstract
The single nucleotide polymorphism (SNP) rs13438494 in intron 24 of PCLO was significantly associated with bipolar disorder in a meta-analysis of genome-wide association studies. In this study, we performed functional minigene analysis and bioinformatics prediction of splicing regulatory sequences to characterize the deep intronic SNP rs13438494. We constructed minigenes with A and C alleles containing exon 24, intron 24, and exon 25 of PCLO to assess the genetic effect of rs13438494 on splicing. We found that the C allele of rs13438494 reduces the splicing efficiency of the PCLO minigene. In addition, prediction analysis of enhancer/silencer motifs using the Human Splice Finder web tool indicated that rs13438494 induces the abrogation or creation of such binding sites. Our results indicate that rs13438494 alters splicing efficiency by creating or disrupting a splicing motif, which functions by binding of splicing regulatory proteins, and may ultimately result in bipolar disorder in affected people.
Highlights
An important role of genetic factors in mental disorders was indicated by family linkage, twin, and adoption studies [1,2,3,4]
In such an effort to search a gene that related to mental disorders, PCLO was identified as an overexpressed gene in the nucleus accumbens of mice subjected to repeated methamphetamine treatment, which can cause severe mental disorders [6]
To avoid amplifying the endogenous PCLO gene, we used the vector-specific primers AcGFP Fw and SV40pA Rv for RT-PCR and exclusively amplified the transcripts produced by the minigene
Summary
An important role of genetic factors in mental disorders was indicated by family linkage, twin, and adoption studies [1,2,3,4]. Genetic studies of mental disorders have been conducted to identify candidate genes, which hold the promise of improving our understanding of the neurobiological basis of mental disorders and may lead to the development of novel therapeutic and protective strategies [5]. In such an effort to search a gene that related to mental disorders, PCLO was identified as an overexpressed gene in the nucleus accumbens of mice subjected to repeated methamphetamine treatment, which can cause severe mental disorders [6]. In the allele frequency obtained within the NCBI SNP database (http://www.ncbi.nlm. nih.gov/snp) for studies representing diverse ethnic groups from Europe, Africa, Japan and China, the rs13438494 has the minor allele frequency of 0.322 (A allele)
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