RESUMO
Epidemiological and genome-wide association studies of severe psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD), suggest complex interactions between multiple genetic elements and environmental factors. The involvement of genetic elements such as Human Endogenous Retroviruses type 'W' family (HERV-W) has consistently been associated with SZ. HERV-W envelope gene (env) is activated by environmental factors and encodes a protein displaying inflammation and neurotoxicity. The present study addressed the molecular characteristics of HERV-W env in SZ and BD. Hundred and thirty-six patients, 91 with BD, 45 with SZ and 73 healthy controls (HC) were included. HERV-W env transcription was found to be elevated in BD (P<10-4) and in SZ (P=0.012) as compared with HC, but with higher values in BD than in SZ group (P<0.01). The corresponding DNA copy number was paradoxically lower in the genome of patients with BD (P=0.0016) or SZ (P<0.0003) than in HC. Differences in nucleotide sequence of HERV-W env were found between patients with SZ and BD as compared with HC, as well as between SZ and BD. The molecular characteristics of HERV-W env also differ from what was observed in Multiple Sclerosis (MS) and may represent distinct features of the genome of patients with BD and SZ. The seroprevalence for Toxoplasma gondii yielded low but significant association with HERV-W transcriptional level in a subgroup of BD and SZ, suggesting a potential role in particular patients. A global hypothesis of mechanisms inducing such major psychoses is discussed, placing HERV-W at the crossroads between environmental, genetic and immunological factors. Thus, particular infections would act as activators of HERV-W elements in earliest life, resulting in the production of an HERV-W envelope protein, which then stimulates pro-inflammatory and neurotoxic cascades. This hypothesis needs to be further explored as it may yield major changes in our understanding and treatment of severe psychotic disorders.
Assuntos
Transtorno Bipolar/virologia , Variações do Número de Cópias de DNA/genética , Retrovirus Endógenos/genética , Genes env/genética , Esquizofrenia/virologia , Toxoplasmose/sangue , Transtorno Bipolar/sangue , Transtorno Bipolar/genética , Estudos de Casos e Controles , Retrovirus Endógenos/metabolismo , Humanos , Esclerose Múltipla/genética , Esclerose Múltipla/virologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esquizofrenia/sangue , Esquizofrenia/genéticaRESUMO
BACKGROUND: Costello syndrome (CS) is a rare multiple congenital abnormality syndrome, associated with failure to thrive and developmental delay. One of the more distinctive features in childhood is the development of facial warts, often nasolabial and in other moist body surfaces. Individuals with CS have an increased risk of malignancy, suggested to be about 17%. Recently, mutations in the HRAS gene on chromosome 11p13.3 have been found to cause CS. METHODS: We report here the results of HRAS analysis in 43 individuals with a clinical diagnosis of CS. RESULTS: Mutations were found in 37 (86%) of patients. Analysis of parental DNA samples was possible in 16 cases for both parents and in three cases for one parent, and confirmed the mutations as de novo in all of these cases. Three novel mutations (G12C, G12E, and K117R) were found in five cases. CONCLUSIONS: These results confirm that CS is caused, in most cases, by heterozygous missense mutations in the proto-oncogene HRAS. Analysis of the major phenotypic features by mutation suggests a potential correlation between malignancy risk and genotype, which is highest for patients with an uncommon (G12A) substitution. These results confirm that mutation testing for HRAS is a reliable diagnostic test for CS.
Assuntos
Anormalidades Múltiplas/diagnóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Anormalidades Múltiplas/genética , Adolescente , Adulto , Criança , Pré-Escolar , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Genótipo , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Síndrome de Noonan/diagnóstico , Síndrome de Noonan/genética , Fenótipo , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Proteínas Tirosina Fosfatases/genética , Proto-Oncogene Mas , SíndromeAssuntos
Mutação , Proteínas Nucleares/genética , Síndrome de Rubinstein-Taybi/genética , Transativadores/genética , Sequência de Bases , Northern Blotting , Southern Blotting , Proteína de Ligação a CREB , Aberrações Cromossômicas , Cromossomos Humanos Par 16 , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Fenótipo , Reação em Cadeia da Polimerase , RNA Mensageiro/análise , Síndrome de Rubinstein-Taybi/diagnóstico , Deleção de SequênciaRESUMO
Synthetic gene transfer vectors can be optimised by combining DNA-binding peptides, cell surface receptor ligands, and fusogenic and nuclear localisation peptides. We have used the phage display technique to identify ligands of the tracheal epithelial cell line CFT-2. The peptides harboured by two phages were selected for transfection studies: peptide 7 (GRGDGDV) that contained the integrin-binding motif RGD, and peptide 9 (RFDSLKV) that was found in six out of 24 phages analysed. Both peptides, fused with the DNA-binding peptide P2 (SPKRSPKRSPKR), enhanced transfection efficiency in cell lines CFT-2, NT-1, NIH-3T3 and ECV-304. In particular, peptide P2-7 increased transfection efficiency from 36. 5% to 44.8% in NIH-3T3 cells and from 10.9% to 14.4% in CFT-2 cells, when compared to transfections performed with peptide P2. Two fusogenic peptides, HA (GLFEAIAEFIEGGWEGLIEGC) and JTS-1 (GLFEALLELLESLWELLLEA), were then added to the complexes and shown to improve transfection efficiency to the same extent. For instance, when combined to peptide P2-7, transfection levels of 54.1% and 55. 2% were attained in NIH-3T3 cells with HA and JTS-1, respectively. The addition of the ligands and fusogenic peptides thus allowed us to construct greatly improved transfection reagents.
