RESUMO
Mutations in PSEN1, PSEN2, or APP genes are known to be causative for autosomal dominant Alzheimer's disease (ADAD). While more than 400 mutations were reported worldwide, predominantly PSEN1, over 40 mutations have been reported in Han Chinese and were associated with earlier onset and more affected family members. Between 2002 and 2018, 77 patients in the neurological clinic of Taipei Veterans General Hospital with a history suggestive of ADAD were referred for mutational analysis. We retrospectively collected demographics, initial symptoms, neurological features and inheritance. We identified 16 patients with PSEN1 and 1 with APP mutation. Among the mutations identified, PSEN1 p.Pro117Leu, p.Met146Ile, p.Gly206Asp, p.Gly209Glu, p.Glu280Lys and p.Leu286Val and APP p.Asp678His were known pathogenic mutations; PSEN1 p.His131Arg and p.Arg157Ser were classified as likely pathogenic and variance of unknown significance respectively. The mean age at onset was 46.2 ± 6.2 years in patients with mutation found. PSEN1 p.Met146Ile, occurred in 56.2% (9/16) of patients with PSEN1 mutations, was the most frequent mutation in the cohort. The additional neurological features occurring in 9 PSEN1 p.Met146Ile index patients were similar with the literature. We found patients with genetic diagnoses were more likely to have positive family history, younger age at onset and less brain white matter hyperintensity.
Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Análise Mutacional de DNA/métodos , Mutação/genética , Presenilina-1/genética , Adulto , Precursor de Proteína beta-Amiloide/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Presenilina-2/genética , Estudos Retrospectivos , TaiwanRESUMO
The Fabry disease-causing mutation, the GLA IVS4+919G>A (designated GLA IVS4), is very prevalent in patients with hypertrophic cardiomyopathy in Taiwan. This X-linked mutation has also been found in patients in Kyushu, Japan and Southeast Asia. To investigate the age and the possible ancestral origin of this mutation, a total of 33 male patients with the GLA IVS4+919G>A mutation, born in Taiwan, Japan, Singapore, Malaysia, Vietnam, and the Fujian and Guangdong provinces of China, were studied. Peripheral bloods were collected, and the Ilumina Infinium CoreExome-24 microarray was used for dense genotyping. A mutation-carrying haplotype was discovered which was shared by all 33 patients. This haplotype does not exist in 15 healthy persons without the mutation. Rather, a wide diversity of haplotypes was found in the vicinity of the mutation site, supporting the existence of a single founder of the GLA IVS4 mutation. The age of the founder mutation was estimated by the lengths of the mutation-carrying haplotypes based on the linkage-disequilibrium decay theory. The first, second, and third quartile of the age estimates are 800.7, 922.6, and 1068.4 years, respectively. We concluded that the GLA IVS4+919G>A mutation originated from a single mutational event that occurred in a Chinese chromosome more than 800 years ago.
Assuntos
Cardiomiopatia Hipertrófica Familiar/genética , Doença de Fabry/genética , alfa-Galactosidase/genética , Adulto , Cardiomiopatia Hipertrófica Familiar/epidemiologia , Cardiomiopatia Hipertrófica Familiar/patologia , China/epidemiologia , Doença de Fabry/epidemiologia , Doença de Fabry/patologia , Genes Ligados ao Cromossomo X/genética , Genótipo , Haplótipos/genética , Humanos , Japão/epidemiologia , Malásia/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Taiwan/epidemiologiaRESUMO
Mutations in RAB18, a member of small G protein, cause Warburg micro syndrome (WARBM), whose clinical features include vision impairment, postnatal microcephaly, and lower limb spasticity. Previously, our Rab18-/- mice exhibited hind limb weakness and spasticity as well as signs of axonal degeneration in the spinal cord and lumbar spinal nerves. However, the cellular and molecular function of RAB18 and its roles in the pathogenesis of WARBM are still not fully understood. Using immunofluorescence staining and expression of Rab18 and organelle markers, we find that Rab18 associates with lysosomes and actively traffics along neurites in cultured neurons. Interestingly, Rab18-/- neurons exhibit impaired lysosomal transport. Using autophagosome marker LC3-II, we show that Rab18 dysfunction leads to aberrant autophagy activities in neurons. Electron microscopy further reveals accumulation of lipofuscin-like granules in the dorsal root ganglion of Rab18-/- mice. Surprisingly, Rab18 colocalizes, cofractionates, and coprecipitates with the lysosomal regulator Rab7, mutations of which cause Charcot-Marie-Tooth (CMT) neuropathy type 2B. Moreover, Rab7 is upregulated in Rab18-deficient neurons, suggesting a compensatory effect. Together, our results suggest that the functions of RAB18 and RAB7 in lysosomal and autophagic activities may constitute an overlapping mechanism underlying WARBM and CMT pathogenesis in the nervous system.
Assuntos
Anormalidades Múltiplas/metabolismo , Autofagia , Catarata/congênito , Doença de Charcot-Marie-Tooth/metabolismo , Córnea/anormalidades , Hipogonadismo/metabolismo , Deficiência Intelectual/metabolismo , Lisossomos/metabolismo , Microcefalia/metabolismo , Sistema Nervoso/metabolismo , Atrofia Óptica/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo , Animais , Catarata/metabolismo , Córnea/metabolismo , Epistasia Genética , Células HEK293 , Humanos , Laminopatias , Camundongos , Neurônios/metabolismo , Células PC12 , Ligação Proteica , Ratos , Ratos Sprague-DawleyRESUMO
Mutations in the gene of RAB18, a member of Ras superfamily of small G-proteins, cause Warburg Micro Syndrome (WARBM) which is characterized by defective neurodevelopmental and ophthalmological phenotypes. Despite loss of Rab18 had been reported to induce disruption of the endoplasmic reticulum structure and neuronal cytoskeleton organization, parts of the pathogenic mechanism caused by RAB18 mutation remain unclear. From the N-ethyl-N-nitrosourea (ENU)-induced mutagenesis library, we identified a mouse line whose Rab18 was knocked out. This Rab18(-/-) mouse exhibited stomping gait, smaller testis and eyes, mimicking several features of WARBM. Rab18(-/-) mice were obviously less sensitive to pain and touch than WT mice. Histological examinations on Rab18(-/-) mice revealed progressive axonal degeneration in the optic nerves, dorsal column of the spinal cord and sensory roots of the spinal nerves while the motor roots were spared. All the behavioral and pathological changes that resulted from abnormalities in the sensory axons were prevented by introducing an extra copy of Rab18 transgene in Rab18(-/-) mice. Our results reveal that sensory axonal degeneration is the primary cause of stomping gait and progressive weakness of the hind limbs in Rab18(-/-) mice, and optic nerve degeneration should be the major pathology of progressive optic atrophy in children with WARBM. Our results indicate that the sensory nervous system is more vulnerable to Rab18 deficiency and WARBM is not only a neurodevelopmental but also neurodegenerative disease.
Assuntos
Anormalidades Múltiplas , Catarata/congênito , Córnea/anormalidades , Etilnitrosoureia/farmacologia , Hipogonadismo , Deficiência Intelectual , Microcefalia , Mutagênese/efeitos dos fármacos , Degeneração Neural/etiologia , Atrofia Óptica , Deleção de Sequência/genética , Proteínas rab de Ligação ao GTP/deficiência , Anormalidades Múltiplas/induzido quimicamente , Anormalidades Múltiplas/genética , Fatores Etários , Animais , Axônios/patologia , Axônios/ultraestrutura , Catarata/induzido quimicamente , Catarata/complicações , Catarata/genética , Modelos Animais de Doenças , Retículo Endoplasmático/patologia , Retículo Endoplasmático/ultraestrutura , Olho/patologia , Hipogonadismo/induzido quimicamente , Hipogonadismo/complicações , Hipogonadismo/genética , Deficiência Intelectual/induzido quimicamente , Deficiência Intelectual/complicações , Deficiência Intelectual/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microcefalia/induzido quimicamente , Microcefalia/complicações , Microcefalia/genética , Microftalmia/etiologia , Microftalmia/genética , Degeneração Neural/patologia , Atrofia Óptica/induzido quimicamente , Atrofia Óptica/complicações , Atrofia Óptica/genética , Doenças do Nervo Óptico/etiologia , Doenças do Nervo Óptico/genética , Desempenho Psicomotor/efeitos dos fármacos , Testículo/patologia , Percepção do Tato/efeitos dos fármacos , Percepção do Tato/genética , Proteínas rab de Ligação ao GTP/genéticaRESUMO
Genetic factors are responsible for the development of the human brain. Certain genetic factors are known to increase the risk of common brain disorders and affect the brain structure. Therefore, even in healthy people, these factors have a role in the development of specific brain regions. Loss-of-function mutations in the RAB18 gene (RAB18) cause Warburg Micro syndrome, which is associated with reduced brain size and deformed brain structures. In this study, we hypothesized that the RAB18 variant might influence regional brain volumes in healthy people. The study participants comprised 246 normal volunteers between 21 and 59 years of age (mean age of 37.8 ± 12.0 years; 115 men, 131 women). Magnetic resonance imaging (MRI) and genotypes of RAB18 rs3765133 were examined for each participant. The differences in regional brain volumes between T homozygotes and A-allele carriers were tested using voxel-based morphometry. The results showed that RAB18 rs3765133 T homozygote group exhibited larger gray matter (GM) volume in the left middle temporal and inferior frontal gyrus of the cerebrum than the A-allele carriers. An opposite effect was observed in both the posterior lobes and right tonsil of the cerebellum, in which the GM volume of RAB18 rs3765133 T homozygotes was smaller than that of the A-allele carriers (all P FWE < 0.05). Our findings suggest that RAB18 rs3765133 polymorphism affects the deve-lopment of specific brain regions, particularly the cerebellum, in healthy people.
Assuntos
Cerebelo/anatomia & histologia , Polimorfismo de Nucleotídeo Único , Proteínas rab de Ligação ao GTP/genética , Adulto , Animais , Estudos de Coortes , Feminino , Lateralidade Funcional , Genótipo , Substância Cinzenta/anatomia & histologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Adulto JovemRESUMO
OBJECTIVES: The forced swim test (FST) is a commonly used model to predict antidepressant efficacy. Uncovering the genetic basis of the model may unravel the mechanism of antidepressant treatment. METHODS: FVB/NJ (FVB) and C57BL/6J (B6) were first identified as the response and non-response strains to fluoxetine (a serotonin-specific reuptake inhibitor antidepressant) treatment in the mouse FST. Simple-interval (SIM) and composite-interval (CIM) mappings were applied to map the quantitative trait loci (QTLs) of the anti-immobility effect of fluoxetine in FST (FST(FLX)) in 865 male B6×FVB-F2 mice. The brain mRNA expressions of the gene with the maximum QTL-linkage signal for FST(FLX) after the FST were compared between B6 and FVB mice and also compared between fluoxetine and saline treatment. The association of the variants in the human homologue of the mouse FST(FLX)-QTL gene with major depressive disorder (MDD) and antidepressant response were investigated in 1080 human subjects (MDD/control = 582/498). RESULTS: One linkage signal for FST(FLX)-QTL was detected at an intronic SNP (rs6215396) of the mouse Zfp326 gene (maximal CIM-LOD = 9.36). The Zfp326 mRNA expression in the FVB thalamus was significantly down-regulated by fluoxetine in the FST, and the higher FVB-to-B6 Zfp326 mRNA expressions in the frontal cortex, striatum and hypothalamus diminished after fluoxetine treatment. Two coding-synonymous SNPs (rs2816881 and rs10922744) in the human homologue of Zfp326, ZNF326, were significantly associated with the 8-week antidepressant treatment response in the MDD patients (Bonferroni-corrected p = 0.004-0.028). CONCLUSIONS: The findings suggest the involvement of the Zfp326 and ZNF326 genes in antidepressant treatment response.
Assuntos
Antidepressivos/farmacologia , Proteínas de Ligação a DNA/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Adulto , Idoso , Animais , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Estudos de Casos e Controles , Proteínas de Ligação a DNA/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Éxons/genética , Feminino , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Polimorfismo Genético/genética , Locos de Características Quantitativas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodutibilidade dos Testes , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Especificidade da Espécie , Natação , Fatores de Transcrição/metabolismo , Resultado do Tratamento , Adulto JovemRESUMO
Amyloid precursor protein (APP) mutations associated with familial Alzheimer's disease (AD) usually lead to increases in amyloid ß-protein (Aß) levels or aggregation. Here, we identified a novel APP mutation, located within the Aß sequence (Aß(D7H)), in a Taiwanese family with early onset AD and explored the pathogenicity of this mutation. Cellular and biochemical analysis reveal that this mutation increased Aß production, Aß42/40 ratio and prolonged Aß42 oligomer state with higher neurotoxicity. Because the D7H mutant Aß has an additional metal ion-coordinating residue, histidine, we speculate that this mutation may promote susceptibility of Aß to ion. When co-incubated with Zn(2+) or Cu(2+), Aß(D7H) aggregated into low molecular weight oligomers. Together, the D7H mutation could contribute to AD pathology through a "double punch" effect on elevating both Aß production and oligomerization. Although the pathogenic nature of this mutation needs further confirmation, our findings suggest that the Aß N-terminal region potentially modulates APP processing and Aß aggregation, and further provides a genetic indication of the importance of Zn(2+) and Cu(2+) in the etiology of AD.
Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Precursor de Proteína beta-Amiloide/genética , Cobre/química , Fragmentos de Peptídeos/genética , Zinco/química , Doença de Alzheimer/metabolismo , Sequência de Aminoácidos , Peptídeos beta-Amiloides/química , Precursor de Proteína beta-Amiloide/química , Ácido Aspártico/química , Ácido Aspártico/genética , Sequência de Bases , Células Cultivadas , Cobre/metabolismo , Feminino , Células HEK293 , Histidina/química , Histidina/genética , Humanos , Pessoa de Meia-Idade , Dados de Sequência Molecular , Mutação , Fragmentos de Peptídeos/química , Polimerização , Taiwan , Zinco/metabolismoRESUMO
UNLABELLED: QBJECTIVES: The aim of the study was to examine the associations between genetic variations in the human PAWR gene and major depressive disorder (MDD) as well as the response to antidepressant treatment. METHODS: Six-hundred and two patients with MDD and 543 controls were included in the study; among the MDD patients, 268 were followed-up for a further 8 weeks in order to assess their response to treatment with selective serotonin reuptake inhibitors (SSRIs). Six polymorphisms (rs17005769, rs4842318, rs7305141, rs2307223, rs8176874 and rs2307220) of the PAWR gene were investigated with regard to their association with MDD and antidepressant treatment efficacy. RESULTS: One polymorphism, rs8176874, was in genotypic (uncorrected P=0.005) and allelic (uncorrected P=0.0015) association with MDD. Several haplotypes spanning rs7305141-rs2307223-rs8176874 were also significantly associated with MDD after correction for multiple testing (corrected P<0.05). However, neither single-marker nor haplotype-based analyses suggested an association between the studied markers and SSRI treatment response. CONCLUSIONS: Genetic variations in the PAWR gene are related to susceptibility to MDD but not to SSRI treatment response.
Assuntos
Transtorno Depressivo Maior/genética , Receptores de Trombina/genética , Adulto , Transtorno Depressivo Maior/tratamento farmacológico , Feminino , Seguimentos , Predisposição Genética para Doença/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/efeitos dos fármacos , Polimorfismo de Nucleotídeo Único/genética , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: Obesity is a multifactorial disease that arises from complex interactions between genetic predisposition and environmental factors. Leptin is central to the regulation of energy metabolism and control of body weight in mammals. METHODOLOGY/PRINCIPAL FINDINGS: To better recapitulate the complexity of human obesity syndrome, we applied N-ethyl-N-nitrosourea (ENU) mutagenesis in combination with a set of metabolic assays in screening mice for obesity. Mapping revealed linkage to the chromosome 6 within a region containing mouse Leptin gene. Sequencing on the candidate genes identified a novel T-to-A mutation in the third exon of Leptin gene, which translates to a V145E amino acid exchange in the leptin propeptide. Homozygous Leptin(145E/145E) mutant mice exhibited morbid obesity, accompanied by adipose hypertrophy, energy imbalance, and liver steatosis. This was further associated with severe insulin resistance, hyperinsulinemia, dyslipidemia, and hyperleptinemia, characteristics of human obesity syndrome. Hypothalamic leptin actions in inhibition of orexigenic peptides NPY and AgRP and induction of SOCS1 and SOCS3 were attenuated in Leptin(145E/145E) mice. Administration of exogenous wild-type leptin attenuated hyperphagia and body weight increase in Leptin(145E/145E) mice. However, mutant V145E leptin coimmunoprecipitated with leptin receptor, suggesting that the V145E mutation does not affect the binding of leptin to its receptor. Molecular modeling predicted that the mutated residue would form hydrogen bond with the adjacent residues, potentially affecting the structure and formation of an active complex with leptin receptor within that region. CONCLUSIONS/SIGNIFICANCE: Thus, our evolutionary, structural, and in vivo metabolic information suggests the residue 145 as of special function significance. The mouse model harboring leptin V145E mutation will provide new information on the current understanding of leptin biology and novel mouse model for the study of human obesity syndrome.
Assuntos
Etilnitrosoureia , Hiperinsulinismo/genética , Leptina/genética , Mutagênese , Mutação , Obesidade Mórbida/genética , Animais , Peso Corporal , Evolução Molecular , Éxons , Predisposição Genética para Doença , Homozigoto , Humanos , Leptina/metabolismo , Camundongos , Receptores para Leptina/genéticaRESUMO
OBJECTIVE: The aim of this study was to examine the associations between genetic variations in the human KCNK2 gene and major depressive disorder (MDD) and response to antidepressant treatment. METHOD: Four hundred and forty-nine patients with MDD and 421 normal controls were included in the study; among the MDD patients, 158 were further followed-up for 8 weeks to assess their response to antidepressant treatment. Five polymorphisms (rs12131478, rs6667764, rs10494994, rs11583745 and rs6686529) of the KCNK2 gene were investigated in terms of their association with MDD and antidepressant treatment efficacy. RESULTS: The genotype frequency of rs6686529 differed significantly between the MDD patients and controls (uncorrected P = 0.00052) and remained statistically significant after correction for multiple comparisons. Individuals with homozygous genotypes (CC or GG) showed greater susceptibility to MDD than those with heterozygous genotypes, indicating a possible heterosis effect of the polymorphism on MDD. In addition, this polymorphism also affected the efficacy of antidepressant treatment: the CC carriers had a greater probability of achieving remission after 8 weeks of treatment than the G-allele carriers [odds ratio = 2.55 (95% confidence interval = 1.11-5.88)]. CONCLUSION: Our findings are in line with those of animal studies, and show that KCNK2 is related to the susceptibility to MDD, and involved in antidepressant treatment response. However, the finding of heterosis association of rs6686529 and MDD may be mechanistic, and further replication studies will be essential.
Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/genética , Canais de Potássio de Domínios Poros em Tandem/genética , Adulto , Idoso , Alelos , Feminino , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Escalas de Graduação PsiquiátricaRESUMO
Disturbance in glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia. Since glutamate receptor interacting protein 1 (GRIP1), a modular protein that enables anchoring of AMPA receptors via its PDZ (postsynaptic density-95/discs large/zona occludens-1) domain and modulates d-serine release, plays an important role in glutamatergic function, this study tests the hypothesis that GRIP1 genetic variants confer susceptibility to schizophrenia. This study investigated whether GRIP1 genetic polymorphisms (rs1038923 and rs4913301) cause a predisposal to schizophrenia. Two GRIP1 polymorphisms were studied in a sample population of 252 people with schizophrenia and 207 normal controls. Significant linkage disequilibrium was obtained between the two polymorphisms. Results demonstrated that neither single marker nor haplotype analysis revealed an association between variants at the GRIP1 locus and schizophrenia, suggesting that it is unlikely that the GRIP1 polymorphisms investigated play a substantial role in conferring susceptibility to schizophrenia. However, association between schizophrenia and other polymorphisms in the GRIP1 gene cannot be totally ruled out as the whole gene was not covered by the two polymorphisms studied.
Assuntos
Proteínas de Transporte/genética , Predisposição Genética para Doença , Proteínas do Tecido Nervoso/genética , Polimorfismo Genético , Esquizofrenia/genética , Adulto , Povo Asiático/etnologia , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-IdadeRESUMO
Glycine acts as an obligatory co-agonist with glutamate on N-methyl-D-aspartate (NMDA) receptors. Brain glycine availability is determined by glycine transporters (GlyT1 or SLC6A9), which mediate glycine reuptake into nerve terminals. Since hypofunction of NMDA receptors has been implicated in the pathophysiology of schizophrenia, this study tests the hypothesis that GlyT1 genetic variants confer susceptibility to schizophrenia. Four GlyT1 polymorphisms were studied in a sample population of 249 people with schizophrenia and 210 normal controls. One polymorphism (rs16831541) was not informative in our Chinese population while the other three polymorphisms (rs1766967, rs2248632 and rs2248253) were analysed with chi-square tests and haplotype analysis. Significant linkage disequilibrium was obtained among the three polymorphisms. Neither single marker nor haplotype analysis revealed an association between variants at the GlyT1 locus and schizophrenia, suggesting that it is unlikely that the GlyT1 polymorphisms investigated play a substantial role in conferring susceptibility to schizophrenia in the Chinese population. Further studies with other GIyT1 variants, relating either to schizophrenia, psychotic symptoms or to therapeutic response in schizophrenia, are suggested.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Glicina/genética , Polimorfismo Genético , Esquizofrenia/genética , Adulto , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Frequência do Gene , Genótipo , Haplótipos , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-IdadeRESUMO
Data from animal studies and from genetic scans in humans suggest that brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, may be involved in the mechanisms underlying substance abuse. The present study tested the hypothesis that the BDNF-gene Val66Met polymorphism is associated with substance abuse. We studied this polymorphism in 103 methamphetamine- and 200 heroin-dependent cases and 122 normal controls. We also considered the association of this polymorphism with age of onset of substance abuse in the heroin-dependent cases. Significant differences in BDNF Val66Met genotype distribution were found between subjects dependent on methamphetamine (P = 0.046) or heroin (P = 0.045) and controls, suggesting that the lower 66Met carrier frequency is associated with substance abuse. Furthermore, in the heroin-dependent group, the Val/Val homozygotes had a later onset of substance abuse compared with the Met allele carriers. The results suggest that the BDNF Val66Met polymorphism or a nearby locus may be involved in the pathogenesis of substance abuse. Our findings support previous genetic scan results showing that BDNF may contribute to substance abuse vulnerability.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Polimorfismo Genético , Transtornos Relacionados ao Uso de Substâncias/genética , Substituição de Aminoácidos , Fator Neurotrófico Derivado do Encéfalo/química , Frequência do Gene , Genótipo , Dependência de Heroína/genética , Humanos , Masculino , Metanfetamina , Polimorfismo de Nucleotídeo Único , Valores de Referência , Caracteres SexuaisRESUMO
From studies of genetic-knockout animals, brain-derived neurotrophic factor (BDNF), a member of the neurotrophin growth-factor family, has been implicated in both alcohol preference and aggressive behaviour. To test whether a BDNF genetic variant may be associated with alcohol-dependent and violent behaviours, we studied Val66Met polymorphism of the BDNF-gene in 110 cases of alcohol-dependence, in 134 extremely violent convicts, and in 149 individuals without psychosis or mood disorders. We also examined the association of this polymorphism with antisocial personality disorder comorbidity in the extremely violent convicts. The results showed that the genotype and allele frequencies for Val66Met polymorphism at the BDNF-gene site did not differ among the three groups. Furthermore, it was not demonstrated that this polymorphism is associated with antisocial personality disorder comorbidity in the extremely violent convicts. Based on these findings, it seems reasonable to suggest that this BDNF-gene Val66Met polymorphism is unlikely to play a major role in the genetic susceptibility to the traits of alcohol-dependence or violence proneness.
Assuntos
Alcoolismo/genética , Fator Neurotrófico Derivado do Encéfalo/genética , Polimorfismo Genético , Violência , Adulto , Povo Asiático/genética , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Reação em Cadeia da PolimeraseRESUMO
Atypical antipsychotics, like clozapine, have fewer extrapyramidal side effects compared with typical antipsychotics, however, such treatment is associated with several adverse metabolic effects such as weight gain, hyperglycemia and hyperlipidemia in patients with schizophrenia. In this study, we investigated the effects of 30-day clozapine treatment on weight change, and serum fasting glucose, cholesterol and triglyceride levels in male BALB/c mice. The results demonstrate that 10.0 mg/kg clozapine group gained significantly less weight but had higher cholesterol compared with controls and the 2.0 mg/kg clozapine group. Our findings indicate the possibility of using mice to study the mechanisms of body weight change and lipid dysregulations induced by clozapine.
Assuntos
Antipsicóticos/farmacologia , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Colesterol/sangue , Clozapina/farmacologia , Triglicerídeos/sangue , Animais , Injeções Intraperitoneais , Lipídeos/sangue , Masculino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
X-box binding protein 1 (XBP1), a critical gene in the endoplasmic reticulum stress response, is located on chromosome 22q12, which has been linked with bipolar disorders in several studies. Recently, associations have been reported between a polymorphism (-116C --> G) in the promoter region of XBP1, and bipolar disorders in both case-control study and family-based association study, however, this finding is not yet confirmed by other research using independent sample populations. To replicate this finding and determine the association between onset age of bipolar disorders and the XBP1 C--116G polymorphism, we investigated the prevalence of this polymorphism in a Chinese population (153 bipolar disorder patients and 174 controls). We were unable, however, to demonstrate a significant association between the C--116G polymorphism and bipolar disorders (P = 0.674 for genotype and P = 0.436 for allele frequency) or age at onset (P = 0.563). Further, no association was demonstrated between this polymorphism and family history in bipolar disorder patients. These negative findings suggest that the XBP1 C--116G polymorphism does not play a major role in the pathogenesis of bipolar disorders in Chinese populations.
Assuntos
Transtorno Bipolar/genética , Proteínas de Ligação a DNA/genética , Proteínas Nucleares/genética , Polimorfismo Genético/genética , Adulto , Idade de Início , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Mutação Puntual , Fatores de Transcrição de Fator Regulador X , Fatores de Transcrição , Proteína 1 de Ligação a X-BoxRESUMO
The learned helplessness (LH) developed after repeat inescapable stress is a well validated animal model of human major depression and is not species specific. c-Fos, the protein product of the protooncogene c-fos, is expressed in neurons under a variety of stressors and could reflect the regional neuronal activation. Using the LH paradigm in mice, we examined c-Fos expression in several brain regions related to stress response or major depression. The LH mice showed significantly lower c-Fos-like immunoreactivity (FLI) in the hippocampus dentate gyrus and the lateral septal nucleus, and higher FLI in the hypothalamic paraventricular nucleus compared with the naive mice. Our finding in the mice LH model supported previous studies in rats showing that the lateral septal nucleus and the hypothalamic paraventricular nucleus are important in LH behaviors. We further demonstrated that hippocampus dentate gyrus, a region important for learning and major depression, may also be involved in the LH behaviors. These related brain regions could provide a basis for further exploration of the molecular mechanisms underlying LH behaviors.
Assuntos
Encéfalo/metabolismo , Desamparo Aprendido , Proteínas Proto-Oncogênicas c-fos/metabolismo , Animais , Comportamento Animal , Encéfalo/patologia , Encéfalo/fisiopatologia , Química Encefálica , Eletrochoque/efeitos adversos , Imuno-Histoquímica/métodos , Masculino , Camundongos , Camundongos Endogâmicos BALB CRESUMO
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, plays an important role in the development, maintenance and function of several neuronal systems. Recent studies have demonstrated that antidepressants, commonly used for panic disorder treatment, can increase central BDNF. In addition, animals with BDNF deficits have higher levels of anxiety when exposed to stressors in comparison to normal controls. The present study tested the hypothesis that the BDNF gene Val66Met polymorphism is associated with panic disorder. In this study, therefore, the incidence of this polymorphism was compared in 103 panic disorder patients and 180 normal controls. The genotype and allele frequencies for the BDNF gene Val66Met polymorphism did not differ comparing the two groups. Furthermore, no association was demonstrated between this BDNF polymorphism and either mitral valve prolapse or agoraphobia in panic disorder patients. These findings suggest that the investigated BDNF polymorphism does not play a major role in the pathogenesis of panic disorder in this Chinese population. Further studies exploring the relationship between genetic variations of BDNF and the cerebral atrophy associated with, and antidepressant treatment response in, panic disorder may be appropriate.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Transtorno de Pânico/genética , Polimorfismo Genético , Adulto , Agorafobia/complicações , Agorafobia/genética , Substituição de Aminoácidos , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Metionina/genética , Pessoa de Meia-Idade , Prolapso da Valva Mitral/complicações , Prolapso da Valva Mitral/genética , Transtorno de Pânico/complicações , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Valina/genéticaRESUMO
Given the implications with respect to neuronal survival and the decreased level of the protein in the striatal region in Parkinson's disease (PD), brain-derived neurotrophic factor (BDNF) may be a candidate gene conferring susceptibility to PD. In a recent study of a Japanese population, a functional BDNF Val66Met polymorphism was associated with PD, however, an analogous investigation of a western population did not replicate this finding. In the present study of a Chinese sample, we have investigated the associations between the BDNF polymorphism and susceptibility to PD and PD onset age. The distribution of the BDNF genotypes and alleles did not differ significantly comparing PD patients and controls. Further, the onset age was not significantly different comparing the three BDNF genotype groups. Thus, our negative findings suggest that it is unlikely that the BDNF Val66Met polymorphism plays a major role in the pathogenesis of PD in the Chinese population. Other BDNF genetic variants, and the association of these variants with PD symptomatology or treatment response, may merit further investigation.
Assuntos
Idade de Início , Fator Neurotrófico Derivado do Encéfalo/genética , Doença de Parkinson/genética , Polimorfismo Genético , Idoso , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Metionina/genética , Pessoa de Meia-Idade , Taiwan/etnologia , Valina/genéticaRESUMO
Preclinical studies have shown that brain-derived neurotrophic factor (BDNF) may be involved in both antidepressant action and the pathophysiology of major depressive disorder (MDD). The present study tested the hypothesis that the BDNF-gene Val66Met polymorphism is associated with MDD, its clinical manifestations, and antidepressant response. To elucidate a genetic predisposition of MDD, we studied BDNF-gene Val66Met polymorphism in 152 MDD patients in 255 normal controls. We also examined the association of this polymorphism and fluoxetine therapeutic response in 110 MDD patients who received a 4-week fluoxetine treatment. No significant differences were demonstrated for the genotype or allele frequency of the BDNF polymorphism comparing the MDD and control groups. Further, no significant differences were noted comparing the three-genotype groups for depressive-cluster symptoms. However, a trend (P = 0.086) to improved 4-week-fluoxetine antidepressant response was demonstrated for heterozygous patients in comparison to homozygous analogs. This finding suggests the BDNF polymorphism investigated plays no major role in the pathogenesis of MDD.