Mutation analysis of DARPP-32 as a candidate gene for schizophrenia.

Abstract

Dopamine- and cAMP-regulated phosphoprotein of relative molecular mass 32kDa (DARPP-32) plays a pivotal role in the signal transduction of several neurotransmitters and neuromodulators that are implicated in the pathophysiology of a variety of neuropsychiatric disorders. A postmortem study reported a significantly reduced DARPP-32 expression in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia, suggesting possible involvement of DARPP-32 in the pathophysiology of schizophrenia. Hence, DARPP-32 was considered as a candidate gene for schizophrenia in this study. We first systemically searched for mutations in the DARPP-32 gene in 50 Han Chinese patients with schizophrenia from Taiwan. Five molecular variants were identified, including a C-to-G substitution (g.-2036C>G) in the putative core promoter that obliterated a predictive AP-2 transcription factor binding site, a G deletion in the untranslated exon 2 (g.1238delG), a G-to-A and an A-to-G substitutions in intron 2 (IVS2+31G>A) and intron 6 (IVS6+32A>G), respectively, and a three-base pair deletion of AGA in exon 6 that resulted in deletion of a glutamate at codon 135 (E135del). Further SNP- and haplotype-based association study in 249 patients and 273 control subjects, however, did not detect association of these markers with schizophrenia. Hence, our results suggest that the reduced DARPP-32 protein in patients with schizophrenia is unlikely caused by mutations in the DARPP-32 gene itself and the DARPP-32 gene is also unlikely a major susceptibility gene for schizophrenia. Nevertheless, the identification of these molecular variants should help the study of gene regulation and structure-function relationship of DARPP-32, and the association study of DARPP-32 gene with other neuropsychiatric disorders.

• Authors: Chen-Hao Li, Hsiao-Mei Liao, Tsai-Wei Hung, Chia-Hsiang Chen
• Journal: Schizophrenia research (Schizophr Res) Vol. 87 Issue 1-3 Pg. 1-5 (Oct 2006) ISSN: 0920-9964 [Print] Netherlands
• PMID: 16750903 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• Dopamine and cAMP-Regulated Phosphoprotein 32
• Cyclic AMP

Topics

• Alleles
• Binding Sites
• Cyclic AMP (genetics, metabolism)
• DNA Fragmentation
• DNA Mutational Analysis (methods)
• DNA Primers (genetics)
• Dopamine and cAMP-Regulated Phosphoprotein 32 (genetics)
• Exons (genetics)
• Female
• Genetic Predisposition to Disease
• Genotype
• Humans
• Inteins (genetics)
• Male
• Middle Aged
• Point Mutation (genetics)
• Polymerase Chain Reaction
• Polymorphism, Single Nucleotide (genetics)
• Schizophrenia (genetics, metabolism, physiopathology)
• Transcriptional Activation (genetics)