A polymorphism in the PDLIM5 gene associated with gene expression and schizophrenia.
ABSTRACT Results of recent DNA microarray analyses of postmortem brains of patients with schizophrenia revealed that expression of the PDZ and LIM domain 5 gene (PDLIM5) is increased. In the present study, we examined whether polymorphisms in PDLIM5 are associated with schizophrenia.
We screened for mutations in PDLIM5 in 24 Japanese patients with schizophrenia and evaluated the associations of the identified polymorphisms with schizophrenia in a Japanese case-control population (total samples, 278 schizophrenia patients and 462 control subjects). Expression of PDLIM5 was quantified by real-time quantitative polymerase chain reaction (PCR) in postmortem prefrontal cortex of 34 schizophrenia patients. Electrophoretic mobility shift assay (EMSA) was performed to examine whether a polymorphism influences nuclear protein binding.
We identified 27 polymorphisms in PDLIM5 and found associations between polymorphisms (rs2433320 and rs2433322) in the 5' region of the gene and schizophrenia (p = .004). Real-time quantitative PCR revealed that these polymorphisms influenced gene expression (p = .007). An EMSA showed that the different alleles of the rs2433320 polymorphism bound differently to nuclear proteins.
These results suggest that PDLIM5 might play a role in genetic susceptibility to schizophrenia.
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ABSTRACT: Dendritic spine morphology is thought to play important roles in synaptic development and plasticity, and morphological derangements in spines are correlated with several neurological disorders. Here, we identified an interaction between Spine-Associated RapGAP (SPAR), a postsynaptic protein that reorganizes actin cytoskeleton and drives dendritic spine head growth, and PDLIM5/Enigma Homolog (ENH), a PDZ-LIM (postsynaptic density-95/Discs large/zona occludens 1-Lin11/Isl-1/Mec3) family member. PDLIM5 has been implicated in susceptibility to bipolar disorder, major depression, and schizophrenia, but its function in neurological disease is poorly understood. We show that PDLIM5 is present in the postsynaptic density, where it promotes decreased dendritic spine head size and longer, filopodia-like morphology. Conversely, RNA interference against PDLIM5 or loss of PDLIM5 interaction with SPAR caused increased spine head diameter. Furthermore, PKC activation promoted delivery of PDLIM5 into dendritic spines and increased its spine colocalization with SPAR. These data reveal new postsynaptic functions for PDLIM5 in shrinkage of dendritic spines that may be relevant to its association with psychiatric illness.Molecular and Cellular Neuroscience 11/2009; 43(2):188-200. DOI:10.1016/j.mcn.2009.10.009 · 3.73 Impact Factor
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ABSTRACT: Polycystic Ovary Syndrome (PCOS) is a polygenic disorder caused by the interaction of susceptible genomic polymorphisms with environmental factors. PCOS, characterized by hyperandrogenism and menstrual abnormalities, has a higher prevalence in women with Bipolar Disorder (BD). Theories explaining this high prevalence have included the effect of PCOS itself or the effect of drugs such as Valproate, which may cause PCOS either directly or indirectly. Incidentally, metabolic abnormalities are observed in both bipolar and PCOS patients. Endophenotypes such as insulin resistance, obesity, and hyperglycemia are common among BD and PCOS patients, suggesting some degree of pathophysiological overlap. Since both BD and PCOS are complex polygenetic diseases, the endophenotype overlap may be the result of common genetic markers. This paper postulates that shared clinical endophenotypes between PCOS and BD indicate common pathophysiological platforms and will review these for the potential of genetic overlap between the two disorders.Medical Hypotheses 07/2009; 73(6):996-1004. DOI:10.1016/j.mehy.2008.12.056 · 1.15 Impact Factor
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ABSTRACT: The postsynaptic density-95/discs large/zone occludens-1 (PDZ) domain and LIM (Lin-11, Isl-1, and Mec-3) domain 5 (PDLIM5) gene has been analyzed as a candidate gene for both schizophrenia and bipolar disorder (BP) in Japanese samples. We performed a family-based association study to test the hypothesis that variants in PDLIM5 increase susceptibility to BP in European-Americans and a meta-analysis to clarify whether there is a single marker consistently contributing to risk for BP. Five single nucleotide polymorphisms in the PDLIM5 gene were genotyped in 290 European-American BP families. Programs Sibling-Transmission/Disequilibrium Test (sib_tdt) and PDTPHASE were used for allelic and haplotypic association, respectively. We carried out a meta-analysis combing our family-based data and case-control data from two Japanese sample sets and from two genome-wide association (GWA) studies. Our association analysis showed no single nucleotide polymorphism associated with BP. A rare haplotype consisted of rs10008257 and rs2433320 had nominal association (P=0.045), which failed to survive correction for multiple tests. The meta-analysis identified a significant allelic association at rs2433320 in all combined samples (excluding overlapped samples in GWA: overall odds ratio=0.897, 95% confidence interval: 0.838-0.961, adjusted P=0.012) and in all Caucasian samples (excluding overlapped samples in GWA: overall odds ratio=0.905, 95% confidence interval: 0.843-0.971, adjusted P=0.032), but not in the Japanese samples. PDLIM5 may have a minor effect on susceptibility to BP in Caucasians. The findings in Japanese need further confirmation in larger independent samples.Psychiatric genetics 07/2008; 18(3):116-21. DOI:10.1097/YPG.0b013e3282fa184b · 2.27 Impact Factor