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We have recently reported the first case of mutation in the core promoter sequence of the human calreticulin gene in a family case of schizoaffective disorder. Remarkably, this gene coincides with a region of suggested linkage at 19p13.2, identified in a whole genome scan [Hamshere et al. (2005); Arch Gen Psychiatry 62;1081-1088]. The identified mutation was located at the conserved position -48 from the transcription start site, and was shown to be of functional effect, resulting in the aberrant expression of the gene. Following screening of the gene in 60 independent cases of schizoaffective disorder, we report novel germ-line mutations at positions -205 C > T and the conserved exon 5 (c: 682 C > T, pro228ser) in two unrelated cases of schizoaffective disorder. These mutations were disease-specific, and as for the -48 G > C mutation, neither was detected in a control population of 370 individuals, indicating a contribution of 3.17% in this sample series. To our knowledge, this is the first instance of disease-specific mutations in schizoaffective disorder, which warrants systematic screening of the regulatory and coding regions of the calreticulin gene in this disorder., ((c) 2009 Wiley-Liss, Inc.)

Aberrant expression of the caveolin-1 (CAV1) gene is associated with Alzheimer's disease (AD) brain. We have recently reported a polymorphic purine stretch located at between 1.8 and 1.5 kb flanking the CAV1 gene, whose alleles and genotypes are associated with late-onset AD. Extra-short homozygote haplotypes were observed that were present only in the AD cases. Following an independent case/control study, we report alleles at the other extreme of the allele range, haplotypes of which were observed to be homozygous across the region in the AD cases. We propose that there is a window for the length of motifs and haplotypes in the controls. Homozygosity for shorter and longer motifs and haplotypes was linked with AD in our study. Our findings elucidate novel predisposing haplotypes at the CAV1 gene purine complex, and confirm the role of this region in the etiopathophysiology of late-onset AD., ((c) 2009 Wiley-Liss, Inc.)

Background: Alzheimer's disease as a neurodegenerative disorder is the commonest type of dementia. A growing number of genes have been reported as the risk factors, which increase the susceptibility to Alzheimer's disease. Apolipoprotein E (APOE), which its ε4 allele has been reported as a risk factor in late onset Alzheimer's disease (AD), is the main cholesterol carrier in the brain. The main goal of this study was to assess the role of APOE genotypes and alleles in AD in Iranian population., Methods: This study was performed in Tehran, Iran from 2007 to 2008. Totally, 154 AD cases and 162 control subjects from Iranian population were genotyped for APOE using PCR method. Genotype and alleles frequencies for APOE were calculated and compared between AD case and control subjects by χ2 or Fisher's exact test. Type one error assumed less than 0.05., Results: The frequency of ε2ε3 genotype was significantly higher in control subjects than AD patients was (13.5% versus 5.2%, P< 0.05) and ε3ε4 genotype frequency was significantly higher in AD cases compared with control subjects. APOE -ε2 allele frequency in cases was lower than that of control subjects but this difference was not significant (4.2% versus 7.7%)., Conclusion: It seems that individuals carrying ε4 allele, develop AD 6.5 times more than non-carriers do (OR= 6.566, 95% CI= 2.89-14.92). It has been reported that ε4 allele acts in dose- age-dependent manner but we have shown that the risk of developing AD in male APOE -ε4 allele carriers is higher than that of female ε4 carriers.

Caveolin 1 (CAV1) is a component of the myelin sheath and the expression of the gene encoding this protein is increased during myelination in Schwann cells and oligodendrocytes. We sought to investigate the homozygote haplotype compartment in a recently identified polymorphic purine complex at the upstream region of the human CAV1 gene in multiple sclerosis (MS). In a case/control study design, the region was characterized in 126 cases of MS diagnosed based on the Revised McDonald diagnostic criteria, and 460 controls. We report a skew in the homozygote haplotype compartment in the cases versus controls both in a qualitative and quantitative respect. Excess homozygosity for haplotypes was observed in the MS cases (corrected p<0.012, OR=2.54, CI 1.14-5.64). Furthermore, we observed eight homozygote haplotypes in the MS cases that were non-existent in the controls (p<0.0003, OR=20.27, CI 2.50-163.8). For the first time, our data highlight the CAV1 upstream purine complex as a novel susceptibility genomic locus in the pathophysiology of MS. Of utmost importance, the region has been conserved across species, including mouse, guinea pig, rhesus macaque, and human. The functional effect of this region remains to be clarified in the future studies.

Crucial interaction of caveolin-1 (CAV1) with beta- and gamma-secretases, and aberrant expression of the gene encoding this protein in Alzheimer's disease (AD) support a role for CAV1 in the pathophysiology of this disease. We report a novel polymorphic purine complex stretching approximately 150 bp of genomic DNA at the 1.5 kb upstream region of the human CAV1 gene, alleles and genotypes of which are associated with sporadic late-onset AD. Extra-short alleles were observed in the case group that were absent in the control subjects. Remarkably, 63% of these alleles were observed to be homozygous in length, forming 23.7% of the homozygote length compartment in the AD cases (chi(2) = 19.08, df = 1, P < 0.000007). Increased homozygosity for length was also observed at this region in the Alzheimer's cases, for the allele lengths shared by the case and control groups [(chi(2) = 30.75, df = 1, P < 0.0000000, OR = 4.54, CI 95% (2.56-8.3)]. This region contains GGAA and GAAA motifs, the consensus binding sites for the Ets and IRF family transcription factors, respectively, and is highly conserved in distantly related non-human primates in respect with location and motif sequence. The effect of this complex sequence on the expression of CAV1, and the related mechanisms in the pathophysiology of AD remain to be clarified., (2008 Wiley-Liss, Inc.)

We previously reported a G>C point mutation located at position -48 within the calreticulin gene core promoter in one individual suffering from paranoid schizophrenia that has also been diagnosed with affective disorder. However, a putative bona fide functional link between this mutation in the calreticulin gene and schizoaffective disorder has remained speculative. We have carried out calreticulin genotyping and psychiatric examination of all available members of the family of the proband and found that three more members carry the -48G>C mutation. Remarkably, two of them develop the disease with an onset and progression that are virtually identical. The third person, too young to have developed fully the disease, nevertheless displays the same symptoms as her affected relatives had at the same early age. Furthermore, transcriptional analysis of the calreticulin promoter in rat cortical neurons shows aberrant increase in transcription in the presence of the -48G>C mutation, both at basal levels and in the presence of valproate and lithium. Our results point to a previously unknown causal role for dysregulation of calreticulin homeostasis in schizoaffective disorder by both genetic and functional analyses, and shed new light on the possible mechanisms of action of valproate and lithium in the treatment of the disease.

Association studies between attention-deficit hyperactivity disorder (ADHD) and the 10-repeat allele of a polymorphism (a 40 bp variable number of tandem repeats) in the dopamine transporter gene (DAT1) have resulted in mixed findings in different populations. We performed a case/control study to clarify the contribution of this allele with ADHD in the Iranian population. No association was observed between the 10-allele and disease (chi(2) = 0.081, P < 0.9). Furthermore, no significant difference was observed in the homozygosity of this allele between the case and control groups (chi(2) = 0.022, P < 0.9). Implication of the dopamine transporter gene in the pathophysiology of ADHD warrants investigation of other functional polymorphisms within this gene in the Iranian ADHD patients., ((c) 2007 Wiley-Liss, Inc.)

Linkage and association studies implicate the dopamine transporter gene (DAT1) in the etiopathophysiology of bipolar disorder. We have recently reported the association between the DAT1 core promoter -67A/T polymorphism and this disorder in a sample of Iranian patients. For the first time, these data support sex dimorphism in the homozygosity for the -67 T-allele between male and female affected cases. The present study was undertaken with a larger sample size of cases (N=240) and controls (N=213) to determine whether there is consistent difference between male and female patients and homozygosity for this allele. The results confirm and strengthen our preliminary observation that homozygosity for the T-allele is a predisposing factor in male patients, but not in females (chi2=8.825, df=1, p=0.003). Moreover, Hardy-Weinberg disequilibrium was observed in the female cases studied (chi2=12.9, df=1, p=0.0003), which may reflect the underlying biology. These findings imply gender dimorphism with respect to the DAT1 -67 alleles and susceptibility to disease.

The expression of the recently identified tumor suppressor gene, DBC2 (Deleted in Breast Cancer 2), is frequently extinguished in breast cancer cells or tissues. Mutation analysis of the essential promoter region, all exons and exon/intron boundaries of the DBC2 gene was performed in 100 sporadic breast cancer cases by PCR-SSCP, and DHPLC, followed by direct sequencing. An additional 17 breast cancer families, who were negative for the BRCA1/2 mutations, were analyzed by direct sequencing. Three novel mutations were observed in the promoter and 5'-untranslated region (UTR) of the gene; a germ-line G>A transition in the promoter at nt -238 from the transcription start site, and two tumor-specific mutations at nt -121C>T and nt +48G>A. No deleterious mutations were detected in the coding sequence of the gene in familial and sporadic breast cancer cases. The sequence variations found within the promoter and 5'-UTR region of the gene warrant expression analysis and screening more tumor samples at this region.

Association between attention deficit hyperactivity disorder (ADHD) and the 10-repeat allele of a polymorphism (a 40 bp variable number of tandem repeats) in the dopamine transporter gene (DAT1) has been reported by several groups. In this study, we examined whether either allele of the DAT1 core promoter -67 functional polymorphism is associated with ADHD in a case/control study. The allele and genotype frequencies of the polymorphism were studied in 110 patients and 120 controls, which were matched on the basis of sex, age and ethnicity. The genotype frequencies in the patients group were as follows: AA 19.2%; AT 65.2%; TT 15.4% vs. the genotype frequencies in the control group: AA 47.5%; AT 43.3%; TT 9.2% [chi2=20.73, df=2, P

Exposure to atypical antipsychotic drugs such as valproate increases the expression of chaperones that assist in the folding of proteins in the endoplasmic reticulum (ER) including calreticulin, GRP78/BiP, GRP94, and PD1. This neuroprotective role may be involved in the pathophysiology of neuropsychiatric disorders such as schizophrenia and bipolar disorder. The 5'-flanking region of the human calreticulin gene was screened in 100 cases of schizophrenia by PCR/SSCA between -485 and +1 basepair (bp) relative to the transcription start site. A G > C point mutation was detected at -48 in a case of paranoid schizophrenia, which was not detected in 280 unrelated control subjects (560 chromosomes). This is the first report of mutation in relation with the calreticulin gene. The -48G > C mutation creates a CpG site at the core promoter region of the gene. The role of this mutation remains to be clarified in the pathophysiology of the disease., (Copyright 2006 Wiley-Liss, Inc.)

An imbalance in the dopaminergic system in humans has been hypothesized to contribute to the pathogenesis of a number of psychiatric illnesses, including bipolar disorder, schizophrenia, and attention deficit hyperactivity disorder. We performed a case/control study on the DAT1 (HUGO approved symbol SL6A3) gene core promoter polymorphism -67A/T to analyze the possible association of either allele of this polymorphism with bipolar disorder. The allele and genotype frequencies of the polymorphism were studied in 136 patients and 163 controls, which were matched on the basis of sex, age, and ethnicity. The genotype frequencies in the patients group were as follows: AA 30.9%; AT 55.1%; TT 14% versus the genotype frequencies in the control group: AA 49%; AT 41.8%; TT 9.2% [chi2 = 10.3, df = 2, OR = 2.15 (95% CI 1.34-3.47, P < or = 0.006]. The T-allele of the -67A/T polymorphism revealed a approximately 1.4-fold excess in the patients group comparing with the controls (P < or = 0.003). For the first time, these findings provide tentative evidence of the contribution of the DAT1 gene core promoter polymorphism to the etiopathophysiology of bipolar disorder at least in the Iranian population that we have studied. Interestingly, no allelic or genotype association was observed in the female patients (P < or = 0.6 and P < or = 0.7, respectively). Replication studies of independent samples and family-based association studies are necessary to further evaluate the significance of our findings., (Copyright 2005 Wiley-Liss, Inc.)

Dysfunction of the central dopaminergic neurotransmission has been suggested to play an important role in the etiology of certain neuropsychiatric disorders such as drug abuse. It has been shown that the dopamine D2 receptor (DRD2) gene dysfunction is associated with multi-drug addiction. Addiction to opium is the most common form of drug abuse in Iran. We studied the allelic association between DRD2 Taq I A polymorphism in 100 opium-dependent Iranian patients and 130 unrelated controls. A 310 bp (base pair) region surrounding Taq I site at the DRD2 locus was amplified by polymerase chain reaction (PCR) and the PCR product was incubated with Taq I restriction enzyme. The A1 allele remained intact while the A2 allele was cut. Significant association was observed between A1 allele and addiction in the patients group (P < 0.0001). Moreover, the frequency of A1A1 genotype was significantly higher in opium users than controls (P < 0.0001). Our result indicates that DRD2 might be involved in the pathophysiology of opium addiction., (Copyright 2005 Wiley-Liss, Inc.)

Dysfunction of the central dopaminergic neurotransmission has been suggested to play an important role in the etiology of schizophrenia. The dopamine transporter (DAT1) mediates the active reuptake of dopamine from the synapses and thereby plays a key role in the regulation of the dopaminergic neurotransmission. In this study, we sought to determine the possible association of the DAT1 gene core promoter polymorphism -67A/T with schizophrenia in a case/control study. The allele and genotype frequencies of the polymorphism were studied in 100 patients and 100 controls, which were matched on the basis of sex, age, and ethnicity. The genotype frequencies in the patients group were as follows: AA 29%; AT 59%; TT 12% versus the genotype frequencies in the control group: AA 57%; AT 38%; TT 5% [chi2 = 16.54, df = 2, OR = 2.25 (95% CI 1.46-3.45, P < or = 0.0003]. For the first time, these findings provide tentative evidence for the contribution of the DAT1 gene core promoter polymorphism to the etiopathophysiology of schizophrenia at least in the Iranian male population that we studied. Replication studies of independent samples and family-based association studies are necessary to further evaluate the significance of our findings., (Copyright 2004 Wiley-Liss, Inc.)

Familial hemophagocytic lymphohistiocytosis (FHL), also known as familial erythrophagocytic lymphohistiocytosis and familial histiocytic reticulosis, is a rare autosomal recessive disorder of early childhood characterized by excessive immune activation. Linkage of the disease gene to an approximately 7.8-cM region between markers D9S1867 and D9S1790 at 9q21.3-22 was identified by homozygosity mapping in four inbred FHL families of Pakistani descent with a combined maximum multipoint LOD score of 6.05. This is the first genetic locus to be described in FHL. However, homozygosity by descent across this interval could not be demonstrated in an additional affected kindred of Arab origin, whose maximum multipoint LOD score was -0.12. The combined sample revealed significant evidence for linkage to 9q markers (LOD score with heterogeneity, 5.00). Identification of the gene(s) involved in the pathogenesis of FHL will contribute to an understanding of the control of T-lymphocyte and macrophage activation, which is central to homeostasis in the immune system.