RESUMEN
BACKGROUND: The genes G72/G30 were recently implicated in schizophrenia in both Canadian and Russian populations. We hypothesized that 1) polymorphic changes in this gene region might be associated with schizophrenia in the Ashkenazi Jewish population and that 2) changes in G72/G30 gene expression might be expected in schizophrenic patients compared with control subjects. METHODS: Eleven single nucleotide polymorphisms (SNPs) encompassing the G72/G30 genes were typed in the genomic deoxyribonucleic acid (DNA) from 60 schizophrenic patients and 130 matched control subjects of Ashkenazi ethnic origin. Case-control comparisons were based on linkage disequilibrium (LD) and haplotype frequency estimations. Gene expression analysis of G72 and G30 was performed on 88 postmortem dorsolateral prefrontal cortex samples. RESULTS: Linkage disequilibrium analysis revealed two main SNP blocks. Haplotype analysis on block II, containing three SNPs external to the genes, demonstrated an association with schizophrenia. Gene expression analysis exhibited correlations between expression levels of the G72 and G30 genes, as well as a tendency toward overexpression of the G72 gene in schizophrenic brain samples of 44 schizophrenic patients compared with 44 control subjects. CONCLUSIONS: It is likely that the G72/G30 region is involved in susceptibility to schizophrenia in the Ashkenazi population. The elevation in expression of the G72 gene coincides with the glutamatergic theory of schizophrenia.
Asunto(s)
Proteínas Portadoras/genética , Expresión Génica/fisiología , Haplotipos/genética , Polimorfismo de Nucleótido Simple , Proteínas/genética , Esquizofrenia/genética , Adolescente , Adulto , Anciano , Proteínas Portadoras/metabolismo , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Humanos , Péptidos y Proteínas de Señalización Intracelular , Judíos/etnología , Judíos/genética , Desequilibrio de Ligamiento , Masculino , Persona de Mediana Edad , Cambios Post Mortem , Corteza Prefrontal/metabolismo , Proteínas/metabolismo , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Población Blanca/etnología , Población Blanca/genéticaRESUMEN
Chordin-like cysteine-rich repeats (CRs) are conserved domains present in an expanding family of secreted proteins that associate with members of the TGF beta superfamily. In this study, we report the molecular cloning and characterization of CHL2 (chordin-like 2), a novel protein closely related to CHL (chordin-like). Both are members of the chordin family of proteins, and contain a signal peptide and three CR domains. We found that recombinant human CHL2 (hCHL2) protein is secreted and binds activin A, but not BMP-2, -4, or -6. Expression of hCHL2 mRNA and protein was detected in a variety of human tissues and is particularly abundant in the uterus. Extensive and complex alternative splicing of hCHL2 was observed in different tissues, resulting in several distinct protein isoforms that vary substantially in the presence of a signal peptide and their content of CR domains. Differential expression of CHL2 variants was observed during myoblast and osteoblast differentiation, implying a role for this gene in these physiological processes.
Asunto(s)
Empalme Alternativo/genética , Proteínas Portadoras/genética , Perfilación de la Expresión Génica , Mioblastos/metabolismo , Osteoblastos/metabolismo , Factor de Crecimiento Transformador beta , Activinas/genética , Activinas/metabolismo , Secuencia de Aminoácidos , Animales , Proteína Morfogenética Ósea 2 , Proteínas Morfogenéticas Óseas/farmacología , Células COS , Proteínas Portadoras/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Línea Celular , Línea Celular Tumoral , Chlorocebus aethiops , Secuencia Conservada/genética , Cisteína/genética , Cisteína/metabolismo , Evolución Molecular , Proteínas de la Matriz Extracelular , Femenino , Humanos , Subunidades beta de Inhibinas/genética , Subunidades beta de Inhibinas/metabolismo , Insulina/farmacología , Masculino , Ratones , Datos de Secuencia Molecular , Mioblastos/citología , Osteoblastos/citología , Unión Proteica , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN/genética , ARN/metabolismo , Proteínas Recombinantes , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homología de Secuencia de AminoácidoRESUMEN
An increasing number of eukaryotic genes are being found to have naturally occurring antisense transcripts. Here we study the extent of antisense transcription in the human genome by analyzing the public databases of expressed sequences using a set of computational tools designed to identify sense-antisense transcriptional units on opposite DNA strands of the same genomic locus. The resulting data set of 2,667 sense-antisense pairs was evaluated by microarrays containing strand-specific oligonucleotide probes derived from the region of overlap. Verification of specific cases by northern blot analysis with strand-specific riboprobes proved transcription from both DNA strands. We conclude that > or =60% of this data set, or approximately 1,600 predicted sense-antisense transcriptional units, are transcribed from both DNA strands. This indicates that the occurrence of antisense transcription, usually regarded as infrequent, is a very common phenomenon in the human genome. Therefore, antisense modulation of gene expression in human cells may be a common regulatory mechanism.
Asunto(s)
Algoritmos , ADN sin Sentido/genética , Genoma Humano , Alineación de Secuencia/métodos , Transcripción Genética/genética , Secuencia de Bases , Análisis por Conglomerados , Sistemas de Administración de Bases de Datos , Bases de Datos de Ácidos Nucleicos , Etiquetas de Secuencia Expresada , Regulación de la Expresión Génica , Humanos , Almacenamiento y Recuperación de la Información/métodos , Datos de Secuencia Molecular , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , ARN sin Sentido/genética , Análisis de Secuencia de ADN/métodos , Células Tumorales CultivadasRESUMEN
Prostate-specific antigen (PSA) and human kallikrein 2 are closely related products of the human kallikrein genes KLK3 and KLK2, respectively. Both PSA and human kallikrein 2 are produced and secreted in the prostate and have important applications in the diagnosis of prostate cancer. We report here the identification of unusual mRNA splice variants of the KLK2 and KLK3 genes that result from inclusion of intronic sequences adjacent to the first exon. The novel proteins encoded by these transcripts, named PSA-linked molecule (PSA-LM) and hK2-linked molecule (K-LM), share only the signal peptide with the original protein product of the respective gene. The mature proteins are entirely different and bear no similarity to the kallikrein family or to other proteins in the databases. As is the case with PSA, PSA-LM is expressed in the secretory epithelial cells of the prostate and is up-regulated in response to androgenic stimulation. A similar pattern of expression is suggested for K-LM.