Genetic Markers as Risk Factors for the Development of Impulsive-Compulsive Behaviors in Patients with Parkinson's Disease Receiving Dopaminergic Therapy.

Impulsive-compulsive and related behavioral disorders (ICD) are drug-induced non-motor symptoms of Parkinson's disease (PD). Recently research has focused on evaluating whether ICD could be predicted and managed using a pharmacogenetic approach based on dopaminergic therapies, which are the main risk factors. The aim of our study was to evaluate the role of candidate genes such as DBH, DRD2, MAOA, BDNF, COMT, SLC6A4, SLC6A3, ACE, DRD1 gene polymorphisms in the pathogenesis of ICD in PD. We compared patients with PD and ICD (n = 49), patients with PD without ICD (n = 36) and a healthy control group (n = 365). ICD was diagnosed using the QUIP questionnaires and specific diagnostic criteria for subtypes of ICD. Genotyping was conducted using a number of PCR techniques and SNaPshot. Statistical analysis was performed using WinPepi and APSampler v3.6 software. PCA testing was conducted using RStudio software v1.4.1106-5. The following substitutions showed statistically significant correlations with PD and ICD: DBH (rs2097629, rs1611115), DRD2 (rs6275, rs12364283, rs1076560), ACE (rs4646994), DRD1 (rs686), BDNF (rs6265), these associations are novel in Russian PD patients. Our findings suggest that polymorphisms in DBH, BDNF, DRD2, ACE genes in Russian subjects are associated with an increased risk of ICD development.

Role of PPARs in Progression of Anxiety: Literature Analysis and Signaling Pathways Reconstruction.

Peroxisome proliferator-activated receptor (PPAR) group includes three isoforms encoded by PPARG, PPARA, and PPARD genes. High concentrations of PPARs are found in parts of the brain linked to anxiety development, including hippocampus and amygdala. Among three PPAR isoforms, PPARG demonstrates the highest expression in CNS, where it can be found in neurons, astrocytes, and glial cells. Herein, the highest PPARG expression occurs in amygdala. However, little is known considering possible connections between PPARs and anxiety behavior. We reviewed possible connections between PPARs and anxiety. We used the Pathway Studio software (Elsevier). Signal pathways were created according to previously developed algorithms. SNEA was performed in Pathway Studio. Current study revealed 14 PPAR-regulated proteins linked to anxiety. Possible mechanism of PPAR involvement in neuroinflammation protection is proposed. Signal pathway reconstruction and reviewing aimed to reveal possible connection between PPARG and CCK-ergic system was conducted. Said analysis revealed that PPARG-dependent regulation of MME and ACE peptidase expression may affect levels of nonhydrolysed, i.e., active CCK-4. Impairments in PPARG regulation and following MME and ACE peptidase expression impairments in amygdala may be the possible mechanism leading to pathological anxiety development, with brain CCK-4 accumulation being a key link. Literature data analysis and signal pathway reconstruction and reviewing revealed two possible mechanisms of peroxisome proliferator-activated receptors involvement in pathological anxiety: (1) cytokine expression and neuroinflammation mechanism and (2) regulation of peptidases targeted to anxiety-associated neuropeptides, primarily CCK-4, mechanism.

Genetic Biomarkers of Panic Disorder: A Systematic Review.

(1) Background: Although panic disorder (PD) is one of the most common anxiety disorders severely impacting quality of life, no effective genetic testing exists; known data on possible genetic biomarkers is often scattered and unsystematic which complicates further studies. (2) Methods: We used PathwayStudio 12.3 (Elsivier, Netherlands) to acquire literature data for further manual review and analysis. 229 articles were extracted, 55 articles reporting associations, and 32 articles reporting no associations were finally selected. (3) Results: We provide exhaustive information on genetic biomarkers associated with PD known in the scientific literature. Data is presented in two tables. Genes COMT and SLC6A4 may be considered the most promising for PD diagnostic to date. (4) Conclusions: This review illustrates current progress in association studies of PD and may indicate possible molecular mechanisms of its pathogenesis. This is a possible basis for data analysis, novel experimental studies, or developing test systems and personalized treatment approaches.

PDE4B gene polymorphism in Russian patients with panic disorder.

BACKGROUND: Panic disorder is a complex disease of unclear etiology but with an apparent genetic component. PDE4B gene product is involved in many cell processes owing to its function-regulation of the level of a second messenger cAMP. PDE4B gene polymorphism has been shown to be associated with some mental disorders including panic disorder. AIMS: The goal of our study was to evaluate the role of 3 SNPs in the PDE4B gene in the development of panic disorder. METHODS: 94 patients diagnosed with panic disorder according to the DSM-IV criteria were enrolled in the study. The population control group included 192 subjects. Genotyping was carried out by real-time PCR with TaqMan probes. RESULTS: The investigated substitutions are not associated with panic disorder in general and in female/male cohorts (p > 0.05). The analysis of complex genotypes demonstrated two protective complex genotypes (rs1040716:A, T + rs10454453:A + rs502958:A and rs1040716:A, T + rs502958:A) associated with panic disorder in general regardless of the patient's gender (p < 0.05). These genotypes did not correlate with the patient's sex. CONCLUSIONS: We found two complex protective genotypes associated with panic disorder. This can be due to the fact that predisposition to the disease are associated with other genes, while PDE4B gene polymorphism reduces their effect.

Association of GA genotype of SNP rs4680 in COMT gene with psoriasis.

Psoriasis is a multigene and multifactorial skin disease with heterogeneous genetic inheritance. Mental disorders participate in the development of psoriasis as predisposing factors; a correlation of dermatological diseases with pathological anxiety and stress was shown. Meanwhile, there are no studies describing molecular mechanisms of the linkages between psycho-emotional disorders and skin diseases. The aim of this study is to find the associations between SNP in genes COMT (rs4680), DBH (rs141116007), CCKAR (rs1800857) and CCKBR (rs1805002), and psoriasis. Patients were selected according to the 10th revision of International Classification of Diseases (L-40). The sample size was 88 patients. The size of the control sample (population control) was 365 people. Genotyping was performed using PCR-RFLP and real-time PCR. Statistical analysis was performed using WinPepi software. Identification of complex genotypes was performed by the Monte Carlo method using APSampler 3.6.1 algorithm. Among the studied genes, only GA genotype of COMT gene is significantly associated with psoriasis [χ2 = 19.163 (p = 1.3E-5), F (p) = 1.2E-5, OR 3.47 (CI 99% = 1.61-7.91)]. At the moment, the functional significance of this phenomenon is difficult to explain.

Psychodermatology: a molecular link between psoriasis and anxiety disorder.

This article describes premises for the development of psychodermatology. An analysis of research literature and data is presented based on the example of psoriasis and anxiety disorder. Protein molecules with altered concentrations in patients with psoriasis and anxiety disorder compared to controls are identified (chemokine [C-C motif] ligand 2, corticotropin-release hormone, growth hormone 1, leptin, and tumor necrosis factor with increased concentration and brain-derived neurotrophic factor with decreased concentration). All molecules are secretory peptides. In the future, the information obtained may make it possible to pursue an in-depth study of the molecular mechanisms underlying psychodermatology.

Biomarkers of migraine: Part 1 - Genetic markers.

BACKGROUND: Migraine is a multifactorial socially significant disease affecting the peripheral and central nervous system. The diagnosis of "migraine" is still the only clinical, and additional methods of inspection are only required to avoid secondary headaches if certain "signs of danger". Accordingly, the search for biomarkers of migraine, confirming the diagnosis, rather than refuting others, is the leading vector in this scientific field. AIM: In this paper we have analyzed the literature data on the genetic markers associated with migraine. METHODS: List of genes was compiled using Pathway Studio 10® software and abstract database ResNet12 ® made by Elsevier. Addition search (last time on 15 March 2016) was performed by using PubMed or TargetInsights. Information about 185 polymorphic loci in 98 genes associated with migraine was extracted and described. RESULTS: The genes associated with migraine could be classified into 8 major groups: homeostasis of blood vessels - 26.5%, metabolism of neurotransmitters - 11.2%, transport and reception of neurotransmitters - 24.5%, neurogenesis - 5.1%, inflammation - 8.2%, sex hormones - 5.1%, ion channels and membrane potential - 11.2%, other - 8.2%. CONCLUSION: These findings parallel the range of mechanisms implicated in migraine pathogenesis.

Agrobacterium tumefaciens responses to plant-derived signaling molecules.

As a special phytopathogen, Agrobacterium tumefaciens infects a wide range of plant hosts and causes plant tumors also known as crown galls. The complexity of Agrobacterium-plant interaction has been studied for several decades. Agrobacterium pathogenicity is largely attributed to its evolved capabilities of precise recognition and response to plant-derived chemical signals. Agrobacterium perceives plant-derived signals to activate its virulence genes, which are responsible for transferring and integrating its Transferred DNA (T-DNA) from its Tumor-inducing (Ti) plasmid into the plant nucleus. The expression of T-DNA in plant hosts leads to the production of a large amount of indole-3-acetic acid (IAA), cytokinin (CK), and opines. IAA and CK stimulate plant growth, resulting in tumor formation. Agrobacterium utilizes opines as nutrient sources as well as signals in order to activate its quorum sensing (QS) to further promote virulence and opine metabolism. Intriguingly, Agrobacterium also recognizes plant-derived signals including γ-amino butyric acid and salicylic acid (SA) to activate quorum quenching that reduces the level of QS signals, thereby avoiding the elicitation of plant defense and preserving energy. In addition, Agrobacterium hijacks plant-derived signals including SA, IAA, and ethylene to down-regulate its virulence genes located on the Ti plasmid. Moreover, certain metabolites from corn (Zea mays) also inhibit the expression of Agrobacterium virulence genes. Here we outline the responses of Agrobacterium to major plant-derived signals that impact Agrobacterium-plant interactions.

Effects of MTHFR gene polymorphism on the clinical and electrophysiological characteristics of migraine.

BACKGROUND: It was previously shown that the MTHFR gene polymorphism correlated with an increased risk of migraine, particularly migraine with aura. The substitution of cytosine for thymine at the position 677 of the MTHFR gene leads to formation of the thermolabile form of the protein and development of hyperhomocysteinemia, which increases the probability of migraine. The purpose of this study was to determine whether the replacement of C677T in the gene MTHFR influenced any particular symptoms of the disease. METHODS: We have analyzed clinical and electrophysiological characteristics of 83 patients with migraine (migraine with aura (MA), 19 patients, and migraine without aura (MO), 64 patients, according to the ICHD-II (2003)) taking into account their genotypes of C677T variant of MTHFR. RESULTS: We have shown that MA was significantly more prevalent among the T-allele carriers (37.2%), as compared to the СС genotype patients (0%), р < 0.0001. Patients with TT genotype were not only more likely to have accompanying symptoms (significant differences were found only for photophobia), but also more sensitive to migraine attack triggers. In RP-VEP test results we observed a trend that the T-allele carriers were presented with the decreased N75/P100 amplitudes and a positive habituation index, as compared to the СС genotype patients. CONCLUSIONS: Thus, according to our data, the MTHFR genotypes are associated with several clinical and electrophysiological characteristics of migraine.

IDentification and Analysis of the Arabidopsis Thaliana Atfas4 Gene Whose Overexpression Results in the Development of A Fasciated Stem.

Using a new pEnLox vector employed to generate gain-of-function mutants in Arabidopsis thaliana, the AtFAS4 mutant has been obtained and analyzed. The mutant is characterized by super-expression of the At1g33390 gene, which leads to the occurrence of a mutant phenotype - stem fasciation. The level of expression of the AtFAS4 gene in normally developing A.thaliana plants is extremely low thus accounting for almost complete absence of information on EST's of this gene. The generated AtFAS4 mutant has permitted full-length cDNA of the At1g33390 gene to be obtained and analyzed for the first time.

Analysis of a new homozygous deletion in the tumor suppressor region at 3p12.3 reveals two novel intronic noncoding RNA genes.

Homozygous deletions or loss of heterozygosity (LOH) at human chromosome band 3p12 are consistent features of lung and other malignancies, suggesting the presence of a tumor suppressor gene(s) (TSG) at this location. Only one gene has been cloned thus far from the overlapping region deleted in lung and breast cancer cell lines U2020, NCI H2198, and HCC38. It is DUTT1 (Deleted in U Twenty Twenty), also known as ROBO1, FLJ21882, and SAX3, according to HUGO. DUTT1, the human ortholog of the fly gene ROBO, has homology with NCAM proteins. Extensive analyses of DUTT1 in lung cancer have not revealed any mutations, suggesting that another gene(s) at this location could be of importance in lung cancer initiation and progression. Here, we report the discovery of a new, small, homozygous deletion in the small cell lung cancer (SCLC) cell line GLC20, nested in the overlapping, critical region. The deletion was delineated using several polymorphic markers and three overlapping P1 phage clones. Fiber-FISH experiments revealed the deletion was approximately 130 kb. Comparative genomic sequence analysis uncovered short sequence elements highly conserved among mammalian genomes and the chicken genome. The discovery of two EST clusters within the deleted region led to the isolation of two noncoding RNA (ncRNA) genes. These were subsequently found differentially expressed in various tumors when compared to their normal tissues. The ncRNA and other highly conserved sequence elements in the deleted region may represent miRNA targets of importance in cancer initiation or progression.

Genomic organisation and tissue specific expression of ABLIM2 gene in human, mouse and rat.

The exon-intron structures of the human, rat and mouse ABLIM2 gene were determined in silico. The experimental verification resulted in the revealing of two mRNA isoforms of the ABLIM2 gene. The isoforms a and b contained 20 exons and 18 exons, respectively. The highest expression of both isoforms was observed in rat brain and eye and in mouse embryos. The 5'-UTR region of the ABLIM2 gene was 127 bp in rat and mouse, but in human, it was 65 bp. The site of polyadenylation was shown to be present at a distance of 682 bp from the stop-codon in human and rat and 684 bp in mouse. The in silico analysis of the gene 5'-region was performed. The high density of brain and CNS specific transcription factors' binding sites in the promoter region was shown for all three organisms. The comparison of the amino acid sequences of the human ABLIM2 and ABLIM1 proteins showed that the number and arrangement of domains (four LIM-domains in the N-end region and the C-end VHP-domain) were similar. The structure of the ABLIM2 proteins was similar in all three organisms. On the basis of our data, it was assumed that the ABLIM2 protein was necessary for the normal functioning of neurons.

Human papilloma viruses and cervical tumours: mapping of integration sites and analysis of adjacent cellular sequences.

BACKGROUND: In cervical tumours the integration of human papilloma viruses (HPV) transcripts often results in the generation of transcripts that consist of hybrids of viral and cellular sequences. Mapping data using a variety of techniques has demonstrated that HPV integration occurred without obvious specificity into human genome. However, these techniques could not demonstrate whether integration resulted in the generation of transcripts encoding viral or viral-cellular sequences. The aim of this work was to map the integration sites of HPV DNA and to analyse the adjacent cellular sequences. METHODS: Amplification of the INTs was done by the APOT technique. The APOT products were sequenced according to standard protocols. The analysis of the sequences was performed using BLASTN program and public databases. To localise the INTs PCR-based screening of GeneBridge4-RH-panel was used. RESULTS: Twelve cellular sequences adjacent to integrated HPV16 (INT markers) expressed in squamous cell cervical carcinomas were isolated. For 11 INT markers homologous human genomic sequences were readily identified and 9 of these showed significant homologies to known genes/ESTs. Using the known locations of homologous cDNAs and the RH-mapping techniques, mapping studies showed that the INTs are distributed among different human chromosomes for each tumour sample and are located in regions with the high levels of expression. CONCLUSIONS: Integration of HPV genomes occurs into the different human chromosomes but into regions that contain highly transcribed genes. One interpretation of these studies is that integration of HPV occurs into decondensed regions, which are more accessible for integration of foreign DNA.