RESUMEN
The AKT1 gene has been associated with the genetic aetiology of schizophrenia. Following the overlap model of bipolar disorder and schizophrenia, we aimed to investigate AKT1 genetic variants and protein expression in both diseases. A total of 679 subjects with European ancestry were included: 384 with schizophrenia, 130 with bipolar disorder and 165 controls. Six single nucleotide polymorphisms (SNPs) were investigated for association with the diseases using single- and multi-locus analyses. AKT1 and AKT2 protein levels were measured in post-mortem brain tissues from ante-mortem diagnosed schizophrenia (n = 30) and bipolar disorder subjects (n = 12) and matched controls. The analysis identified a significant global distortion in schizophrenia (P = 0.0026) and a weak association in bipolar disorder (P = 0.046). A sliding window procedure showed a five-SNP haplotype (TCGAG) to be associated with schizophrenia (P = 1.22 x 10(-4)) and bipolar disorder (P = 0.0041) and a four-SNP haplotype (TCGA) with the combined sample (1.73 x 10(-5)). On the basis of selected genotypes, a significant difference in protein expression emerged between subjects (P < 0.02). In conclusion, our findings, by showing the involvement of the AKT1 gene in both schizophrenia and bipolar disorder, support the role of AKT1 in the genetics of both disorders and add support to the view that there is some genetic overlap between them.
Asunto(s)
Trastorno Bipolar/genética , Encéfalo/metabolismo , Haplotipos/genética , Proteínas Proto-Oncogénicas c-akt/genética , Esquizofrenia/genética , Adulto , Trastorno Bipolar/metabolismo , Estudios de Casos y Controles , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas c-akt/metabolismo , Valores de Referencia , Esquizofrenia/metabolismo , Estadísticas no ParamétricasRESUMEN
Capture of cellular mRNA by mobile elements has been an evolutionary catalyst for the spread of genes and a cause of cancer development. Here we present evidence that an orphan gene, FAM8A1 (family with sequence similarity 8), was captured by a retrovirus, followed by multiple retrotransposition events, during primate evolution between 45 and 58 million years ago. This represents the first record of cellular mRNA transduction in humans. The human gene is localized on chromosome 6p23 with five related pseudogenes (FAM8A2P-A6P), each inserted within a human endogenous retrovirus (HERV). Only the functional FAM8A1 gene is expressed and displays a ubiquitous mRNA and a testis-specific transcript present in the haploid phase of spermatogenesis. The structural features of the FAM8A1 pseudogenes include two short sequences of similarity between the FAM8A1 mRNA and the HERV sequences at both the 5' and 3' integration sites. These hallmarks suggest an alternative model to account for the capture of FAM8A1 cellular mRNA by HERV-K, involving illegitimate recombination events at the two sites of sequence similarity during reverse transcription. Unlike previous models, which assume at least one step of retroviral integration in the genome, our model is consistent with in vitro observations showing that multiple template switches occur among packaged viral transcripts. This leads to the speculation that, in some cases, cellular mRNAs may have been captured through similar processes involved in the retroviral life cycle.
Asunto(s)
Retrovirus Endógenos/genética , Evolución Molecular , Primates/genética , Proteínas/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Northern Blotting , Bovinos , Pollos , ADN/química , ADN/genética , ADN Complementario/química , ADN Complementario/genética , Femenino , Conversión Génica , Expresión Génica , Transferencia de Gen Horizontal , Humanos , Masculino , Proteínas de la Membrana , Ratones , Datos de Secuencia Molecular , Mutación , Filogenia , Seudogenes/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Alineación de Secuencia , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Homología de Secuencia de Ácido Nucleico , Distribución Tisular , Tortugas , XenopusRESUMEN
1. A sample of patients having attempted to commit suicide by using violent methods (hanging, jumping) was investigated according to the following procedure: for each patient, some evaluative tests (the MADRS, the SCL 90 and an agressivity scale) were administered and DSM III diagnosis was provided as well as the therapeutical orientation. 2. The 5 HIAA' level was measured in the CSF soon after the suicide attempt except for patients with rachis fracture or exposed to a cerebral oedeme. 3. Results were compared to those of a control group composed with patients having operated with rachi-anesthesia for orthopedic surgery. 4. The preliminary results show that 5 HIAA' levels were lower for suicide patients except for one schizophrenic patient. 5. This study suggests the possible link between a low 5 HIAA' level in CSF and the clinical aspects of severe suicidal behaviour.