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BACKGROUND: Despite extensive research in the past decades, the influence of genetics on cognitive functions in schizophrenia remains unclear. Dystrobrevin-binding protein 1 (DTNBP1) is one of the most promising candidate genes in schizophrenia. An association of DTNBP1 with cognitive dysfunction, particularly memory impairment, has been reported in a number of studies. However, the results remain inconsistent. The aim of this study was to measure the association between DTNBP1 polymorphisms and cognitive domains in a well-characterized sample. METHODS: Ninety-one clinically stable schizophrenia outpatients underwent a battery of cognitive tests. Six single nucleotide polymorphisms (SNPs) of DTNBP1 were genotyped in all participants. Statistical and multivariate analyses were performed. RESULTS: Factor analysis revealed 4 factors corresponding to distinct cognitive domains, namely sustained attention, set-shifting, executive functioning, and memory. We found a significant association of the rs909706 polymorphism with attention (p = 0.030) and a nonsignificant trend for set-shifting (p = 0.060). The other SNPs and haplotypes were not associated with cognitive function. DISCUSSION: Replication of this finding in a larger sample is needed in order to confirm the importance of this particular polymorphism in the genetics of schizophrenia, particularly the distinct cognitive domains. In conclusion, the present study supports the involvement of DTNBP1 in the regulation of cognitive processes and demonstrates association in particular with sustained attention and set-shifting in schizophrenia patients.
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Atención , Trastornos del Conocimiento/genética , Proteínas Asociadas a la Distrofina/genética , Esquizofrenia/genética , Psicología del Esquizofrénico , Adolescente , Adulto , Anciano , Trastornos del Conocimiento/psicología , Disbindina , Función Ejecutiva , Análisis Factorial , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Memoria , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
BACKGROUND: Although sarcoidosis and celiac disease are both chronic immunologic disorders involving multiple organ systems, reports about association of diseases in individual patients are sparse. While sarcoidosis is a chronic granulomatous disease presumably reflecting an exaggerated response to an unknown antigen, celiac disease is a T cell-driven disease triggered by ingestion of gluten, a protein composite found in wheat and related grains. CASE PRESENTATION: We present three cases with a longstanding history of sarcoidosis that have been additionally diagnosed with celiac-like enteropathy. In two cases, celiac disease was established applying celiac-specific serology and duodenal histology, while one case was revealed as an AIE-75-positive autoimmune enteropathy. The HLA-DR3/DQ2 haplotype was confirmed in both celiac patients, hence confirming previous data of linkage disequilibrium as a cause for disease association. Remarkably, one celiac patient presented with granulomatous nodulae in the ileum, thus reflecting an intestinal sarcoid manifestation. In contrast the patient with an autoimmune enteropathy, was HLA-DQ9/DQ6-positive, also arguing against CD. CONCLUSIONS: Associations of sarcoidosis and celiac disease are rare but do occur. Determining the HLA status in patients with complex autoimmune associations might help classifying involved disease entities.
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Enfermedad Celíaca/diagnóstico , Enfermedades Pulmonares/complicaciones , Poliendocrinopatías Autoinmunes/diagnóstico , Sarcoidosis/complicaciones , Adulto , Biomarcadores/sangre , Enfermedad Celíaca/sangre , Enfermedad Celíaca/complicaciones , Enfermedad Celíaca/inmunología , Diagnóstico Diferencial , Femenino , Antígenos HLA-DQ/sangre , Haplotipos , Humanos , Enfermedades Pulmonares/sangre , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/inmunología , Persona de Mediana Edad , Poliendocrinopatías Autoinmunes/sangre , Poliendocrinopatías Autoinmunes/complicaciones , Poliendocrinopatías Autoinmunes/inmunología , Sarcoidosis/sangre , Sarcoidosis/diagnóstico , Sarcoidosis/inmunologíaRESUMEN
BACKGROUND/AIMS: Alcohol dependence is a common severe psychiatric disorder with a multifactorial etiology. Since the completion of the human genome project and with the increased availability of high-throughput genotyping, multiple genetic risk factors for substance-related disorders, including alcohol dependence, have been identified, but not all results could be replicated. METHODS: We systematically review the clinical literature on genetic risk factors for alcohol dependence and alcohol-related phenotypes, including candidate gene-based studies, linkage studies and genome-wide association studies (GWAS). RESULTS: Irrespectively of the methodology employed, the most robust findings regarding genetic risk factors for alcohol dependence concern genetic variations that affect alcohol metabolism. GWAS confirm the importance of the alcohol dehydrogenase gene cluster on chromosome 4 in the genetic risk for alcohol dependence with multiple variants that exert a small, but cumulative influence. A single variant with strong influence on individual risk is the aldehyde dehydrogenase 2 ALDHD2*2 variant common in Asian populations. Other robust associations have been found with previously uncharacterized genes like KIAA0040, and such observations can lead to the identification of thus far unknown signaling pathways. Converging evidence also points to a role of glutamatergic, dopaminergic and serotonergic neurotransmitter signaling in the risk for alcohol dependence, but effects are small, and gene-environment interactions further increase the complexity. CONCLUSION: With few exceptions like ALDH2*2, the contribution of individual genetic variants to the risk for alcohol-related disorders is small. However, the concentration of risk variants within neurotransmitter signaling pathways may help to deepen our understanding of the underlying pathophysiology and thereby contribute to develop novel therapeutic strategies.
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Alcoholismo/genética , Alcoholismo/metabolismo , Aldehído Deshidrogenasa/genética , Aldehído Deshidrogenasa Mitocondrial , Estudios de Asociación Genética , Ligamiento Genético , Humanos , Proteínas/genética , Factores de RiesgoRESUMEN
Impaired axonal transport in motor neurons has been proposed as a mechanism for neuronal degeneration in motor neuron disease. Here we show linkage of a lower motor neuron disease to a region of 4 Mb at chromosome 2p13. Mutation analysis of a gene in this interval that encodes the largest subunit of the axonal transport protein dynactin showed a single base-pair change resulting in an amino-acid substitution that is predicted to distort the folding of dynactin's microtubule-binding domain. Binding assays show decreased binding of the mutant protein to microtubules. Our results show that dysfunction of dynactin-mediated transport can lead to human motor neuron disease.
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Cromosomas Humanos Par 2 , Proteínas Asociadas a Microtúbulos/genética , Enfermedad de la Neurona Motora/genética , Secuencias de Aminoácidos , Animales , Transporte Biológico , Centrómero/metabolismo , Clonación Molecular , Drosophila , Complejo Dinactina , Ligamiento Genético , Humanos , Ratones , Ratones Transgénicos , Microtúbulos/metabolismo , Modelos Genéticos , Modelos Moleculares , Mutación , Unión Proteica , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Transporte de Proteínas , Recombinación GenéticaRESUMEN
OBJECTIVE: Our pilot study evaluates the impact of environmental factors, such as nutrition and smoking status, on epigenetic patterns in a disease-associated gene. METHOD: We measured the effects of malnutrition and cigarette smoking on proopiomelanocortin (POMC) promoter-specific DNA methylation in female patients with and without anorexia nervosa (AN). POMC and its derived peptides (alpha melanocyte stimulating hormone and adrenocorticotropic hormone) are implicated in stress and feeding response. Promoter-specific DNA methylation of the POMC gene was determined in peripheral blood mononuclear cells of 54 healthy female control subjects, 40 underweight patients with AN, and 21 weight-restored patients with AN using bisulfite sequencing. Malnutrition was characterized by plasma leptin. RESULTS: POMC promoter-specific DNA methylation was not affected by diagnosis or nutritional status but significantly negatively associated with cigarette smoking. CONCLUSIONS: Although malnutrition may be expected to reduce DNA methylation through its effects on one-carbon metabolism, our negative results are in line with several in vitro and clinical studies that did not show a direct relation between gene-specific DNA methylation and folate levels. In contrast, smoking has been repeatedly reported to alter DNA methylation of specific genes and should be controlled for in future epigenetic studies.
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Anorexia Nerviosa/genética , Metilación de ADN/genética , Desnutrición/genética , Proopiomelanocortina/genética , Fumar/genética , Adolescente , Adulto , Índice de Masa Corporal , Estudios de Casos y Controles , Islas de CpG/genética , Epigénesis Genética , Femenino , Humanos , Leptina/sangre , Desnutrición/sangre , Proyectos Piloto , Regiones Promotoras GenéticasRESUMEN
The microtubule motor cytoplasmic dynein and its activator dynactin drive vesicular transport and mitotic spindle organization. Dynactin is ubiquitously expressed in eukaryotes, but a G59S mutation in the p150Glued subunit of dynactin results in the specific degeneration of motor neurons. This mutation in the conserved cytoskeleton-associated protein, glycine-rich (CAP-Gly) domain lowers the affinity of p150Glued for microtubules and EB1. Cell lines from patients are morphologically normal but show delayed recovery after nocodazole treatment, consistent with a subtle disruption of dynein/dynactin function. The G59S mutation disrupts the folding of the CAP-Gly domain, resulting in aggregation of the p150Glued protein both in vitro and in vivo, which is accompanied by an increase in cell death in a motor neuron cell line. Overexpression of the chaperone Hsp70 inhibits aggregate formation and prevents cell death. These data support a model in which a point mutation in p150Glued causes both loss of dynein/dynactin function and gain of toxic function, which together lead to motor neuron cell death.
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Trastornos Heredodegenerativos del Sistema Nervioso/genética , Trastornos Heredodegenerativos del Sistema Nervioso/metabolismo , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/fisiología , Neuronas Motoras/metabolismo , Animales , Apoptosis/genética , Células COS , Células Cultivadas , Chlorocebus aethiops , Complejo Dinactina , Dineínas/metabolismo , Proteínas HSP70 de Choque Térmico/biosíntesis , Proteínas HSP70 de Choque Térmico/genética , Humanos , Proteínas Asociadas a Microtúbulos/química , Proteínas Asociadas a Microtúbulos/metabolismo , Microtúbulos/química , Microtúbulos/genética , Microtúbulos/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Mutación PuntualRESUMEN
The number of studies on imaging genetics has risen considerably over the last few years, and haplotypes are being increasingly applied as a model to increase the explained variance in functional brain activation. Haplotypes, however, are not always the preferable approach. While such highly complex models have a greater capacity for fitting data, they might also lead to over-fitting. This study compares individual single nucleotide polymorphisms (SNPs) with haplotypes by applying both models to effects of catechol-O-methyltransferase (COMT), one of the most extensively studied genes in psychiatric research and imaging genetics, on the central processing of affective cues. To our knowledge, this is the first study to compare haplotypes and SNPs of the COMT gene in an imaging genetics study. The model comparison in this study is based on the Akaike Information Criterion (AIC) and the Bayesian Information Criterion (BIC), introducing the novel concepts of posterior evidence ratio maps and best model maps. Findings reveal the simplest model, comprising only the well studied COMT Val(158)Met polymorphism, to be the most informative one. These results do not necessarily mean that haplotype models are in general inferior to individual SNP analysis. They do underline, however, that techniques for model comparison such as the ones used in this study need to be employed to establish whether the increase in likelihood provided by a more complex haplotype-based model is large enough to warrant the increase in model complexity.
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Afecto/fisiología , Encéfalo/fisiopatología , Catecol O-Metiltransferasa/genética , Emociones/fisiología , Haplotipos/genética , Red Nerviosa/fisiología , Polimorfismo de Nucleótido Simple/genética , Adulto , Femenino , Humanos , MasculinoRESUMEN
Major depression is conditionally linked to a polymorphism of the human serotonin transporter gene (SLC6A4). During the presentation of aversive, but not pleasant, pictures, healthy carriers of the SLC6A4 short (s) allele showed stronger activation of the amygdala on functional magnetic resonance imaging. s carriers also showed greater coupling between the amygdala and the ventromedial prefrontal cortex, which may contribute to the abnormally high activity in the amygdala and medial prefrontal cortex seen in major depression.
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Alelos , Amígdala del Cerebelo/fisiología , Heterocigoto , Glicoproteínas de Membrana/fisiología , Proteínas de Transporte de Membrana/fisiología , Proteínas del Tejido Nervioso/fisiología , Corteza Prefrontal/fisiología , Anciano , Amígdala del Cerebelo/irrigación sanguínea , Emociones , Humanos , Imagen por Resonancia Magnética , Masculino , Glicoproteínas de Membrana/genética , Proteínas de Transporte de Membrana/genética , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Oxígeno/sangre , Estimulación Luminosa , Corteza Prefrontal/irrigación sanguínea , Proteínas de Transporte de Serotonina en la Membrana PlasmáticaRESUMEN
Reward processing depends critically on dopaminergic neurotransmission in the ventral striatum. The common polymorphism val(158)met of catechol-O-methyltransferase (COMT) accounts for significant interindividual variations in dopamine (DA) degradation, although the direct effect of COMT on striatal DA might be limited. Using fMRI we assessed the influence of COMT val(158)met genotype on brain activations elicited by the anticipation of monetary gains and losses in forty-four healthy volunteers. We found that the met(158) allele, which is presumably linked to higher synaptic DA levels, was associated with higher responses in ventral striatum to loss incentives. There was a linear relationship between the number of met(158) alleles and ventral striatal activity. Furthermore, we observed a similar gene-dose effect in the anterior temporal cortex, a region that has been linked to the coupling of sensory information with emotional contents. Temporal cortex also showed enhanced connectivity to the ventral striatum during the processing of incentive stimuli. Increased ventral striatal reactivity to loss incentives related to the met(158) allele might contribute to the observed association of the met(158) allele to higher loss aversion behaviour. Current evidence and our results are compatible with an interpretation that construes this effect of COMT genotype on striatal reactivity as a result of a cortico-striatal interaction.
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Atención/fisiología , Catecol O-Metiltransferasa/genética , Corteza Cerebral/fisiología , Cuerpo Estriado/fisiología , Potenciales Evocados/fisiología , Intuición/fisiología , Recompensa , Adulto , Femenino , Genotipo , Humanos , Imagen por Resonancia Magnética , MasculinoRESUMEN
We describe clinical, electrophysiological, histopathological and molecular features of a unique disease caused by mutations in the glycyl-tRNA synthetase (GARS) gene. Sixty patients from five multigenerational families have been evaluated. The disease is characterized by adolescent onset of weakness, and atrophy of thenar and first dorsal interosseus muscles progressing to involve foot and peroneal muscles in most but not all cases. Mild to moderate sensory deficits develop in a minority of patients. Neurophysiologically confirmed chronic denervation in distal muscles with reduced compound motor action potentials were features consistent with both motor neuronal and axonal pathology. Sural nerve biopsy showed mild to moderate selective loss of small- and medium-sized myelinated and small unmyelinated axons, although sensory nerve action potentials were not significantly decreased. Based on the presence or absence of sensory changes, the disease phenotype was initially defined as distal spinal muscular atrophy type V (dSMA-V) in three families, Charcot-Marie-Tooth disease type 2D (CMT2D) in a single family, and as either dSMA-V or CMT2D in patients of another large family. Linkage to chromosome 7p15 and the presence of disease-associated heterozygous GARS mutations have been identified in patients from each of the five studied families. We conclude that patients with GARS mutations present a clinical continuum of predominantly motor distal neuronopathy/axonopathy with mild to moderate sensory involvement that varies between the families and between members of the same family. Awareness of these overlapping clinical phenotypes associated with mutations in GARS will facilitate identification of this disorder in additional families and direct future research toward better understanding of its pathogenesis.
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Glicina-ARNt Ligasa/genética , Enfermedades Musculares/genética , Adolescente , Adulto , Brazo , Biopsia/métodos , Enfermedad de Charcot-Marie-Tooth/etnología , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Niño , Electromiografía/métodos , Salud de la Familia , Femenino , Humanos , Pierna , Masculino , Persona de Mediana Edad , Debilidad Muscular/etnología , Debilidad Muscular/genética , Debilidad Muscular/fisiopatología , Músculo Esquelético/fisiopatología , Atrofia Muscular Espinal/etnología , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/fisiopatología , Enfermedades Musculares/etnología , Enfermedades Musculares/fisiopatología , Mutación , Conducción Nerviosa/fisiología , Fenotipo , Nervio Sural/patologíaRESUMEN
The dopamine transporter (DAT) plays a pivotal role in maintaining optimal dopamine signaling. DAT-overactivity has been linked to various neuropsychiatric disorders yet so far the direct pathological consequences of it has not been fully assessed. We here generated a transgenic rat model that via pronuclear microinjection overexpresses the DAT gene. Our results demonstrate that DAT-overexpression induces multiple neurobiological effects that exceeded the expected alterations in the corticostriatal dopamine system. Furthermore, transgenic rats specifically exhibited behavioral and pharmaco-therapeutic profiles phenotypic of repetitive disorders. Together our findings suggest that the DAT rat model will constitute a valuable tool for further investigations into the pathological influence of DAT overexpression on neural systems relevant to neuropsychiatric disorders.
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Modelos Animales de Enfermedad , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Enfermedades del Sistema Nervioso/psicología , Regulación hacia Arriba , Animales , Masculino , Ratones , Microinyecciones , Enfermedades del Sistema Nervioso/genética , Ratas , Ratas TransgénicasRESUMEN
RATIONALE: Alcohol dependence is characterized by the development of tolerance, withdrawal symptoms, and craving for alcohol. Chronic alcohol consumption causes neuroadaptive changes in the central dopaminergic and serotonergic system, which are partially reversible after detoxification. The severity and time-course of recovery of these neuroadaptive changes may depend on the genetic constitution of monoamine transporters and receptors and contribute to the relapse risk of alcoholics. OBJECTIVES: To assess the interaction between the genetic constitution and the in vivo availability of dopamine and serotonin transporters and receptors, chronic alcohol intake, alcohol craving and withdrawal. METHODS: Review of brain imaging studies that assess the genotype and availability of dopamine and serotonin transporters in detoxified alcoholics and healthy control subjects. RESULTS: Chronic alcohol intake induced neuroadaptive reductions in striatal dopamine transporter (DAT) availability, which were reversible during early abstinence. A polymorphism of the DAT gene (SLC6A3) was associated with the in vivo transporter availability and with the severity of alcohol withdrawal. Neurotoxic reductions in 5-HTT protein expression were limited to homozygous carriers of the long allele in the 5-HTT gene (SCL6A4) regulatory region and correlated with negative mood states. CONCLUSION: Genetic constitution interacts with the in vivo availability of central dopamine and serotonin transporters during alcohol detoxification and may affect the severity of alcohol withdrawal and clinical depression.
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Alcoholismo/genética , Dopamina/metabolismo , Glicoproteínas de Membrana/genética , Proteínas de Transporte de Membrana/genética , Proteínas del Tejido Nervioso/genética , Alcoholismo/diagnóstico por imagen , Alcoholismo/metabolismo , Alcoholes/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encéfalo/fisiopatología , Causalidad , Genotipo , Humanos , Redes Neurales de la Computación , Neurobiología/métodos , Farmacogenética/métodos , Fenotipo , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Tomografía Computarizada de Emisión de Fotón Único/métodosRESUMEN
Conventional duplex sonography is a well-established method for the assessment of the brain-supplying arteries in acute stroke. However, ultrasound (US) remains inconclusive in a significant number of stroke patients. Recently, two new US parameters, the cerebral transit time (cTT) and the global cerebral blood flow volume (CBF), have been introduced. In the present study, we investigated the diagnostic and prognostic value of both parameters in stroke patients. Conventional duplex examinations of the extra- and intracranial brain-supplying arteries and measurement of cTT and CBF were performed in 50 consecutive stroke patients within 24 h after symptom onset and compared with US findings in 22 age-matched healthy controls. Neurological deficits and the degree of disability were graded using several stroke scores, and were re-evaluated for outcome measure after 1 year. CBF and cTT were not assessable in 26% and 20% of the patients, respectively. Compared with the healthy control group, stroke patients showed a significant reduction of CBF and prolongation of cTT. More than 50% of patients with otherwise normal routine duplex examination had abnormal CBF or cTT findings. Furthermore, there was a strong correlation between the reduction of global CBF and the outcome after 1 year. Sonographic assessment of the CBF and cTT are additional parameters that might increase the diagnostic sensitivity of US in stroke patients, and may have prognostic relevance.
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Circulación Cerebrovascular , Accidente Cerebrovascular/diagnóstico por imagen , Enfermedad Aguda , Anciano , Tiempo de Circulación Sanguínea , Arterias Cerebrales/diagnóstico por imagen , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Sensibilidad y Especificidad , Índice de Severidad de la Enfermedad , Accidente Cerebrovascular/fisiopatología , Ultrasonografía Doppler Transcraneal/métodosRESUMEN
The nicotinic system is involved in the pathophysiology of schizophrenia. However, very little is known about its genetic basis and how it relates to clinical symptoms and potentially pharmacological intervention. Here, we investigated five single nucleotide polymorphisms (SNPs) [rs3826029] [rs2337506] [rs982574] [rs904952] [rs2337980] of the cholinergic nicotinic receptor gene, alpha 7 subunit (CHRNA7) and their association to schizophrenia. We found an association with rs904952 (p = 0.009) in a German sample of 224 schizophrenic patients and 224 healthy control subjects. The same trend was shown in an independent Georgian sample of 50 schizophrenic patients, 57 first order unaffected relatives, and 51 healthy controls. In addition, visual backward masking (VBM), a sensitive test for early visual information processing, was assessed in the Georgian sample. In line with prior studies, VBM performance deficits were much more pronounced in schizophrenic patients and their unaffected relatives compared to healthy controls (schizophrenic patients: 156 ms; unaffected relatives: 60 ms; healthy controls: 33 ms). VBM was strongly correlated with SNP rs904952 (H[2] = 7.3, p = 0.026). Our results further support the notion that changes in the nicotinic system are involved in schizophrenia and open the avenue for pharmacological intervention.
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Antipsychotic-induced weight gain has emerged as a serious complication in the treatment of patients with atypical antipsychotic drugs. The cannabinoid receptor 1 (CNR1) is expressed centrally in the hypothalamic region and associated with appetite and satiety, as well as peripherally. An antagonist of CNR1 (rimonabant) has been effective in causing weight loss in obese patients indicating that CNR1 might be important in antipsychotic-induced weight gain. Twenty tag SNPs were analyzed in 183 patients who underwent treatment (with either clozapine, olanzapine, haloperidol, or risperidone) for chronic schizophrenia were evaluated for antipsychotic-induced weight gain for up to 14 weeks. The polymorphism rs806378 was nominally associated with weight gain in patients of European ancestry treated with clozapine or olanzapine. 'T' allele carriers (CT+TT) gained more weight (5.96%), than the CC carriers (2.76%, p=0.008, FDR q-value=0.12). This translated into approximately 2.2 kg more weight gain in patients carrying the T allele than the patients homozygous for the CC genotype (CC vs CT+TT, 2.21+/-4.51 vs 4.33+/-3.89 kg; p=0.022). This was reflected in the allelic analysis (C vs T allele, 3.84 vs 5.83%, p=0.035). We conducted electrophoretic mobility shift assays which showed that the presence of the T allele created a binding site for arylhydrocarbon receptor translocator (ARNT), a member of the basic helix-loop-helix/Per-Arnt-Sim protein family. In this study, we provide evidence that the CNR1 gene may be associated with antipsychotic-induced weight gain in chronic schizophrenia patients. However, these observations were made in a relatively small patient population; therefore these results need to be replicated in larger sample sets.
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Antipsicóticos/efectos adversos , Obesidad/inducido químicamente , Obesidad/genética , Polimorfismo Genético/genética , Receptor Cannabinoide CB1/genética , Aumento de Peso/efectos de los fármacos , Adolescente , Adulto , Translocador Nuclear del Receptor de Aril Hidrocarburo/metabolismo , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes/efectos de los fármacos , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Obesidad/metabolismo , Unión Proteica/genética , Aumento de Peso/genética , Población Blanca , Adulto JovenRESUMEN
RATIONALE: In major depression, prefrontal regulation of limbic brain areas may be a key mechanism that is impaired during the processing of affective information. This prefrontal-limbic interaction has been shown to be modulated by serotonin (5-HTT) genotype, indicating a higher risk for major depressive disorder (MDD) with increasing number of 5-HTT low-expression alleles. OBJECTIVE: Functional magnetic resonance imaging was used to assess neural response to uncued unpleasant affective pictures in 21 unmedicated patients with MDD compared to 21 matched healthy controls, taking into account genetic influences of the 5-HTT (SCL6A4) high- and low-expression genotype. RESULTS: Healthy controls displayed greater prefrontal activation (BA10) to uncued negative pictures compared to patients with MDD. While in healthy controls prefrontal (BA10) activation and BA10-amygdala coupling increased with the number of 5-HTT low-expression risk alleles, this effect was abolished, and even reversed, in patients with MDD. In MDD, connectivity decreased with severity of depressive symptoms (HAMD total score). CONCLUSION: These findings suggest that increased medial prefrontal (BA10) activation and BA10-amygdala connectivity may counteract the risk for MDD in healthy carriers of 5-HTT low-expression alleles, while this protective factor might be lost in patients who actually suffer from MDD. Prefrontal-limbic regulation in risk populations could be a target of early interventions and should be the focus of further research.
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Amígdala del Cerebelo/fisiopatología , Trastorno Depresivo Mayor/genética , Trastorno Depresivo Mayor/patología , Corteza Prefrontal/fisiopatología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Adulto , Afecto/fisiología , Amígdala del Cerebelo/irrigación sanguínea , Mapeo Encefálico , Estudios de Casos y Controles , Señales (Psicología) , Femenino , Genotipo , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Vías Nerviosas/irrigación sanguínea , Vías Nerviosas/fisiopatología , Oxígeno/sangre , Estimulación Luminosa/métodos , Corteza Prefrontal/irrigación sanguínea , Regiones Promotoras Genéticas/genética , Escalas de Valoración Psiquiátrica , Psicofísica/métodos , Índice de Severidad de la Enfermedad , Estadística como Asunto , Factores de TiempoRESUMEN
Schizophrenia is a complex disorder, where family, twin and adoption studies have been demonstrating a high heritability of the disease and that this disease is not simply defined by several major genes but rather evolves from addition or potentiation of a specific cluster of genes, which subsequently determines the genetic vulnerability of an individual. Linkage and association studies suggest that a genetic vulnerablility, is not forcefully leading to the disease since triggering factors and environmental influences, i.e. birth complications, drug abuse, urban background or time of birth have been identified. This has lead to the assumption that schizophrenia is not only a genetically defined static disorder but a dynamic process leading to dysregulation of multiple pathways. There are several different hypothesis based on several facets of the disease, some of them due to the relatively well-known mechanisms of therapeutic agents. The most widely considered neurodevelopmental hypothesis of schizophrenia integrates environmental influences and causative genes. The dopamine hypothesis of schizophrenia is based on the fact that all common treatments involve antidopaminergic mechanisms and genes such as DRD2, DRD3, DARPP-32, BDNF or COMT are closely related to dopaminergic system functioning. The glutamatergic hypothesis of schizophrenia lead recently to a first successful mGlu2/3 receptor agonistic drug and is underpinned by significant findings in genes regulating the glutamatergic system (SLC1A6, SLC1A2 GRIN1, GRIN2A, GRIA1, NRG1, ErbB4, DTNBP1, DAAO, G72/30, GRM3). Correspondingly, GABA has been proposed to modulate the pathophysiology of the disease which is represented by the involvement of genes like GABRA1, GABRP, GABRA6 and Reelin. Moreover, several genes implicating immune, signaling and networking deficits have been reported to be involved in the disease, i.e. DISC1, RGS4, PRODH, DGCR6, ZDHHC8, DGCR2, Akt, CREB, IL-1B, IL-1RN, IL-10, IL-1B. However, molecular findings suggest that a complex interplay between receptors, kinases, proteins and hormones is involved in schizophrenia. In a unifying hypothesis, different cascades merge into another that ultimately lead to the development of symptoms adherent to schizophrenic disorders.
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Esquizofrenia/patología , Dopamina/metabolismo , Ácido Glutámico/metabolismo , Humanos , Modelos Neurológicos , Fosfatidilinositol 3-Quinasas/metabolismo , Proteína Reelina , Esquizofrenia/enzimología , Esquizofrenia/genética , Esquizofrenia/inmunología , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Identification of gene-environment and gene-gene interactions has become increasingly important in understanding psychiatric disorders. Dysfunction of central serotonergic neurotransmission has been implicated in alcoholism, depression, and anxiety. We review the literature on nonhuman primates that assesses the interaction between the genetic constitution of the regulatory region ofthe serotonin transporter (5-HTT) and environmental factors. Prospective studies in nonhuman primates that underwent social stress found a reduction of theserotonin turnover rate among carriers of one or two short alleles in a functional polymorphism of the 5-HTT promoter. In these primates, brain imaging studies showed a relative increase in the availability of raphe serotonin transporters. A low serotonin turnover rate and a high availability of serotonin transporters were associated with reduced response to excessive alcohol intake, anxiety, and impulsive aggression. Animal experiments point to a relationship between serotonergic dysfunction, negative mood states, and excessive alcohol intake, which may in part be mediated by reduced alcohol-induced sedation.
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Conducta Animal/fisiología , Encéfalo/patología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/genética , Serotonina/metabolismo , Agresión/fisiología , Alcoholismo/genética , Alcoholismo/metabolismo , Animales , Mapeo Encefálico , Ambiente , Polimorfismo GenéticoRESUMEN
Impaired axonal transport has been postulated to play a role in the pathophysiology of multiple neurodegenerative disorders. In this report, we describe the results of clinical and neuropathological studies in a family with an inherited form of motor neuron disease caused by mutation in the p150Glued subunit of dynactin, a microtubule motor protein essential for retrograde axonal transport. Affected family members had a distinct clinical phenotype characterized by early bilateral vocal fold paralysis affecting the adductor and abductor laryngeal muscles. They later experienced weakness and atrophy in the face, hands, and distal legs. The extremity involvement was greater in the hands than in the legs, and it had a particular predilection for the thenar muscles. No clinical or electrophysiological sensory abnormality existed; however, skin biopsy results showed morphological abnormalities of epidermal nerve fibers. An autopsy study of one patient showed motor neuron degeneration and axonal loss in the ventral horn of the spinal cord and hypoglossal nucleus of the medulla. Immunohistochemistry showed abnormal inclusions of dynactin and dynein in motor neurons. This mutation of dynactin, a ubiquitously expressed protein, causes a unique pattern of motor neuron degeneration that is associated with the accumulation of dynein and dynactin in neuronal inclusions.