Regulation des alternativen Spleißens von Tau Exon 10 durch Phosphorylierung von Spleißfaktoren

Tau ist ein Mikrotubuli- assoziiertes Protein, dessen Expression im Nervensystem des Menschen der Regulation durch alternatives Spleißen unterliegt. Das Exon 10 dieses Gens, welches für einen Teil der Mikrotutuli- bindenden Domäne kodiert, ist ein für Erwachsene spezifisches Kassettenexon. Mutationen, die den Einschluss von Exon 10 verstärken, resultieren in der Produktion von Tau- Protein, das vier Mikrotubuli- bindende Aminosäuresequenzwiederholungen enthält. Diese Mutationen scheinen in ursächlichem Zusammenhang mit der Frontotemporalen Demenz mit Parkinsonismus gekoppelt an Chromosom 17 (FTDP- 17) zu stehen. In dieser Arbeit konnte mittels Transfektionsexperimenten gezeigt werden, dass die Verwendung von Exon 10 durch ein komplexes Zusammenspiel der CDC- ähnlichen Kinase Clk2, einer SR- Proteinkinase, und des SR- ähnlichen Proteins humaner Transformer 2- b (Htra2- b) reguliert wird. Kotransfektionsexperimente legen den Schluss nahe, dass diese Regulation über mehrere ineinandergreifende Prozesse abläuft. Die Kinase Clk2 scheint dabei sowohl direkt durch Posphorylierung bzw. Hyperphosophorylierung von Htra2- b als auch indirekt durch Einfluss auf die alternative Expression der Htra2- b Isoformen in den Regulationsmechanismus einzugreifen. Phosphorylierung von SR- Proteinen führt zu deren Freisetzung aus den nukleären Speicherkomponenten, den speckles, und damit zur Aktivierung der Spleißreaktion, während sowohl eine Hyper- als auch eine Hypophosphorylierung in der Regel einen hemmenden Einfluss auf Spleißen ausüben. Kontrollierte Phosphorylierung scheint demnach zu einer regulierbaren Veränderung von prä- mRNA- Prozessierungswegen zu führen. Eine Interpretation dieser Resultate könnte als Grundlage für die Entwicklung neuer therapeutischer Konzepte verwendet werden

NCAM1, TACR1 and NOS Genes and Temperament: A Study on Suicide Attempters and Controls

Suicide, one of the leading causes of death among young adults, seems to be plausibly modulated by both genetic and personality factors. The aim of this study was to dissect the potential association between genetics and temperament in a sample of 111 suicide attempters and 289 healthy controls. We focused on 4 genes previously investigated in association with suicide on the same sample: the nitric oxide synthase 1 and 3 (NOS1 and NOS3), the neuronal cell adhesion molecule 1 (NCAM1), and the tachykinin receptor 1 (TACR1) genes. In particular, we investigated whether a set of genetic variants in these genes (NOS1 : rs2682826, rs1353939, rs693534; NOS3 : rs2070744, rs1799983, rs891512; NCAM1 : rs2301228, rs1884, rs1245113, rs1369816, rs2196456, rs584427; TACR1 : rs3771810, rs3771825, rs726506, rs1477157) were associated with temperamental traits at the Temperament and Character Inventory (TCI). No strong evidence was found for the association between TCI personality traits and the polymorphisms considered in the 4 genes, with the exception of an association between reward dependence trait and the rs2682826 SNP in NOS1 in the healthy sample. However, this result could be plausibly interpreted as a false-positive finding. In conclusion, our study did not support the thesis of a direct modulation of these genes on temperament; however, further studies on larger samples are clearly required in order to confirm our preliminary findings and to exclude any possible minor influence. Copyright (C) 2011 S. Karger AG, Base

Tyrosine Hydroxylase and DOPA Decarboxylase Gene Variants in Personality Traits

Personality influences several characteristics of normal and pathologic behaviors and it is associated with neurotransmitter systems that are under genetic control. The dopaminergic system has been proposed to play a role in the modulation of personality traits. In the present study, variants of the tyrosine hydroxylase (TH) and DOPA decarboxylase (DDC) genes (for TH: rs3842727, rs6356; for DDC: rs1451371, rs1470750, rs998850) were investigated in 111 suicide attempters and 289 healthy subjects to assess the involvement of the dopaminergic synthesis pathway in personality traits. No strong evidence was found for the associations between personality and TH or DDC in overall tests. An interaction effect of genotype and diagnosis was present, with TH and DDC SNPs having a greater effect on the respective personality dimensions in the group of suicide attempters. Because of the risk of false positives, these findings should be interpreted with highest caution. Direct replication attempts within independent groups of suicide attempters will help to resolve this question. Copyright (C) 2009 S. Karger AG, Base

No association of a set of candidate genes on haloperidol side effects.

We previously investigated a sample of patients during an active phase of psychosis in the search for genetic predictors of haloperidol induced side effects. In the present work we extend the genetic association analysis to a wider panel of genetic variations, including 508 variations located in 96 genes. The original sample included 96 patients. An independent group of 357 patients from the CATIE study served as a replication sample. Outcomes in the investigation sample were the variation through time of: 1) the ESRS and UKU total scores 2) ESRS and UKU subscales (neurologic and psychic were included) related to tremors and 3) ESRS and UKU subscales that do not relate to tremors. Outcome in the replication sample was the presence vs absence of motoric side effects from baseline to visit 1 (~ one month of treatment) as assessed by the AIMS scale test. Rs2242480 located in the CYP3A4 was associated with a different distribution of the UKU neurologic scores through time (permutated p = 0.047) along with a trend for a different haloperidol plasma levels (lower in CC subjects). This finding was not replicated in the CATIE sample. In conclusion, we did not find conclusive evidence for a major association between the investigated variations and haloperidol induced motoric side effects

High-risk Allele for Herpes Labialis Severity at the IFNL3/4 Locus is Associated With Vestibular Neuritis

Objective: Vestibular neuritis (VN) is a peripheral vestibular disorder leading to a sudden loss of unilateral vestibular function. Although the underlying etiological mechanisms for disease development are not yet known, there is evidence that a latent infection with herpes simplex virus type 1 (HSV-1) might be involved. The polymorphism rs12979860 has been associated with the severity of recurrent herpes labialis and hepatitis C virus (HCV) clearance and treatment outcome and is located within the first intron of the IFNL4 gene on chromosome 19.q13.2. This case control study was conducted to evaluate the association of rs12979860 with VN occurrence. Methods: DNA was extracted from EDTA blood of 151 VN patients and 1,775 healthy controls. Genotyping of rs12979860 was performed using iPLEX and MassARRAY Matrix Assisted Laser Desorption Ionization—Time of Flight (MALDI-TOF) mass spectrometry. For association analyses, an additive, dominant and recessive logistic regression model was calculated, using age and sex as covariates. Results: A significant association of rs12979860 with VN was obtained for the additive [OR = 1.51 (1.18–1.92); p = 9.23 × 10−4] and dominant models [OR = 2.15 (1.48–3.13); p = 5.86 × 10−5], with the T allele being more frequent in the VN group. Conclusion: By detecting a significant association of the rs12979860-T risk allele for herpes labialis severity with susceptibility to VN, this study gives further indirect evidence for an involvement of HSV-1 in VN pathology, thereby strengthening the virus hypothesis

A Variation in FGF14 Is Associated with Downbeat Nystagmus in a Genome-Wide Association Study

Downbeat nystagmus (DBN) is a frequent form of acquired persisting central fixation nystagmus, often associated with other cerebellar ocular signs, such as saccadic smooth pursuit or gaze-holding deficits. Despite its distinct clinical features, the underlying etiology of DBN often remains unclear. Therefore, a genome-wide association study (GWAS) was conducted in 106 patients and 2609 healthy controls of European ancestry to identify genetic variants associated with DBN. A genome-wide significant association (p < 5 × 10−8) with DBN was found for a variation on chromosome 13 located within the fibroblast growth factor 14 gene (FGF14). FGF14 is expressed in Purkinje cells (PCs) and a reduction leads to a decreased spontaneous firing rate and excitability of PCs, compatible with the pathophysiology of DBN. In addition, mutations in the FGF14 gene cause spinocerebellar ataxia type 27. Suggestive associations (p < 1 × 10−05) could be detected for 15 additional LD-independent loci, one of which is also located in the FGF14 gene. An association of a region containing the dihydrofolate reductase (DHFR) and MutS Homolog 3 (MSH3) genes on chromosome 5 was slightly below the genome-wide significance threshold. DHFR is relevant for neuronal regulation, and a dysfunction is known to induce cerebellar damage. Among the remaining twelve suggestive associations, four genes (MAST4, TPPP, FTMT, and IDS) seem to be involved in cerebral pathological processes. Thus, this GWAS analysis has identified a potential genetic contribution to idiopathic DBN, including suggestive associations to several genes involved in postulated pathological mechanisms of DBN (i.e., impaired function of cerebellar PCs)

MALDI mass spectrometry imaging - Diagnostic pathways and metabolites for renal tumor entities

BACKGROUND Correct tumor subtyping of primary renal tumors is essential for treatment decision in daily routine. Most of the tumors can be classified on morphology alone. Nevertheless, some diagnoses are difficult and further investigations are needed for correct tumor subtyping. Beside histochemical investigations high mass resolution matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) can detect new diagnostic biomarkers and hence improve the diagnostic. PATIENTS AND METHODS Formalin-fixed paraffin embedded (FFPE) tissue specimens from clear cell renal cell carcinoma (ccRCC, n=552), papillary RCC (pRCC, n=122), chromophobe RCC (chRCC, n=108) and renal Oncocytoma (rO, n=71) were analyzed by high mass resolution matrix-assisted laser desorption/ionization (MALDI) fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometry imaging (MSI). SPACiAL pipeline was executed for automated co-registration of histological and molecular features. Pathway enrichment and pathway topology analysis were performed to determine significant differences between RCC subtypes. RESULTS We discriminated the four histological subtypes (ccRCC, pRCC, chRCC and rO) and established the subtype specific pathways and metabolic profiles. RO showed an enrichment of pentose phosphate, taurine and hypotaurine, glycerophospholipid, amino sugar and nucleotide sugar, fructose and mannose, glycine, serine and threonine pathways. ChRCC is defined by enriched pathways including the amino sugar and nucleotide sugar, fructose and mannose, glycerophospholipid, taurine and hypotaurine, glycine, serine and threonine pathways. Pyrimidine, amino sugar and nucleotide sugar, glycerophospholipid and glutathione pathways are enriched in ccRCC. Furthermore, we detected enriched phosphatidylinositol and glycerophospholipid pathways in pRCC. CONCLUSION In summary, we performed a classification system with a mean accuracy in tumor discrimination of 85,13%. Furthermore, we detected tumor specific biomarkers for the four most common primary renal tumors by MALDI-MSI. This method is a useful tool in differential diagnosis and in biomarker detection

Genome-Wide Association Study in Vestibular Neuritis: Involvement of the Host Factor for HSV-1 Replication

Objective: In order to identify genetic variants associated with vestibular neuritis, a common cause of peripheral vertigo with a potential causative link to the reactivation of herpes simplex type 1 (HSV-1), we conducted a genome-wide association study.Methods: Association was assessed using approximately 8 million variants. 131 patients with vestibular neuritis and 2,609 controls of European ancestry were included.Results: Genome-wide associations with vestibular neuritis were detected in 4 regions containing protein coding genes assignable to two functional groups: virus hypothesis and insulin metabolism. Genes of set 1 are related to viral processes: nuclear receptor subfamily 3 group C member 2 (NR3C2) is a receptor for mineralocorticoids and glucocorticoids and was shown to be a host factor for HSV-1 replication. Ankyrin repeat domain 30A (ANKRD30A) encodes a host factor for human immunodeficiency virus-1 (HIV-1) infection. It shows rapid evolution and is induced by interferon stimulation. Mediator complex 30 (MED30), an important member of the mediator complex, has been shown to be involved in replication of HIV-1, a knockdown leading to impaired viral replication. The second set of genes LIM homeobox transcription factor 1 alpha (LMX1A), solute carrier family 30 member 8 (SLC30A8) is associated with insulin metabolism and resistance, a feature of some patients in whom type 2 diabetes is an accompanying comorbidity of vestibular neuritis.Conclusions: Using a GWAS approach to evaluate the etiology of vestibular neuritis these findings provide another piece of evidence that it may be caused by a viral inflammation