RESUMEN
Catechol-O-methyltransferase is a candidate in the predisposition to schizophrenia both because of its function and the position of its gene. A multipoint non-parametric linkage analysis and a transmission disequilibrium test were performed on 42 multiplex families genotyped for Pml I and Bcl I polymorphisms using two definitions of the affected phenotype. Neither linkage nor preferential transmission of any allele or haplotype was detected, failing to replicate previous positive findings.
Asunto(s)
Catecol O-Metiltransferasa/genética , Catecol O-Metiltransferasa/metabolismo , Desequilibrio de Ligamiento/genética , Esquizofrenia , Alelos , Femenino , Francia/epidemiología , Expresión Génica , Predisposición Genética a la Enfermedad , Haplotipos/genética , Humanos , Masculino , Polimorfismo Genético/genética , Esquizofrenia/enzimología , Esquizofrenia/epidemiología , Esquizofrenia/genéticaRESUMEN
Catechol-O-methyltransferase (COMT) catalyzes the degradation of catecholamines and could therefore play a role in the etiology of schizophrenia. Moreover, microdeletions including the COMT locus have been found in schizophrenics presenting typical features of the velo-cardio-facial syndrome. In the present work, five single-strand conformation polymorphisms were detected in exons of the COMT gene. The linkage disequilibria between the polymorphisms were estimated, and the genotypic frequencies were calculated on a sample of 126 to 137 schizophrenics and 136 to 140 controls, depending on the marker. Patients and controls were matched for ethnicity and geographical origin. A trend toward association was found between schizophrenia and (i) genotype 11 of the Pml I polymorphism (p = 0.034; OR = 1.82); (ii) haplotype 1-2 for the Pml I and Bcl I polymorphisms (p = 0.022; OR = 1.75). The Pml I polymorphism is in complete linkage disequilibrium with the common Met-->Val(158) substitution, which affects the activity of the enzyme. This finding suggests a possible minor effect of COMT in a multifactorial threshold model of vulnerability to schizophrenia.
Asunto(s)
Catecol O-Metiltransferasa/genética , Desequilibrio de Ligamiento , Esquizofrenia/genética , Regiones no Traducidas 3' , Regiones no Traducidas 5' , Adulto , Alelos , Estudios de Casos y Controles , Cromosomas Humanos Par 22 , Exones , Femenino , Francia , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo Conformacional Retorcido-SimpleRESUMEN
A decrease in age of onset of schizophrenia through consecutive family generations (anticipation) has been found in several studies. Anticipation is known to result from expansion of CAG repeats in genes that determine several neurodegenerative disorders. In a previous study we analysed 26 unilineal two-generation French pedigrees and found clinical evidence of anticipation. A 10-year mean reduction in age of onset of schizophrenia was found in the second generation compared with the parental generation. The repeat expansion detection method was used to screen for CAG expansion in 21 of the 26 families with evidence of anticipation for the disease and in 59 sporadic schizophrenics and 59 controls. Comparison of the frequency distributions of CAG/CTG repeat size observed in schizophrenics and controls showed no significant difference, even when we considered familial (P = 0.23) and sporadic (P = 0.25) affected individuals separately. These results do not support the association between long CAG repeats and schizophrenia. However, the possibility that expansions with fewer than 40 repeats are involved in schizophrenia cannot be excluded.
Asunto(s)
Esquizofrenia/genética , Repeticiones de Trinucleótidos , Adulto , Interpretación Estadística de Datos , Femenino , Francia , Humanos , Masculino , Persona de Mediana Edad , Linaje , Reacción en Cadena de la Polimerasa/métodosRESUMEN
Anticipation has been described in bipolar affective disorder (BPAD). However, there are conflicting results from association studies screening for a link between BPAD and CAG/CTG repeat expansions, the molecular basis of anticipation in several hereditary neurodegenerative disorders. Here, the repeat expansion detection (RED) method was used to screen for CAG repeat expansion in 119 French BPAD patients. Western blotting was also used to search for polyglutamine stretches, encoded by CAG expansion, among proteins, extracted from lymphoblastoid cell lines, from six selected familial cases. Maximum CAG/CTG repeat length did not differ significantly (P = 0.38) between the 119 BPAD patients and the 88 controls included in the study. Several categories of subgroups were used, none of which showed significant association with a long repeat. Nor was a specific protein with an unusually long polyglutamine stretch (lower detection limit, approximately 33 polyglutamines) detected in cell lysates from the familial cases studied. In conclusion, an association between a long CAG/CTG repeat and BPAD in the French population sample studied was not found. Nonetheless, a short repeat (<40 repeats) might still be implicated, and this possibility warrants further study.
Asunto(s)
Trastorno Bipolar/genética , Repeticiones de Trinucleótidos , Adulto , Edad de Inicio , Western Blotting , Femenino , Francia , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Péptidos/análisis , Reacción en Cadena de la PolimerasaRESUMEN
BACKGROUND: Genes encoding proteins involved in serotonergic metabolism are major candidates in association studies of mood disorders and suicidal behavior. This association study explores whether the tryptophan hydroxylase (TPH) gene, which codes for the rate-limiting enzyme of serotonin biosynthesis, is a susceptibility factor for manic-depressive illness, with or without a history of suicide attempts. METHODS: The TPH intron 7 A218C polymorphism was determined using a polymerase chain reaction-based method in DNA samples from 152 patients with bipolar disorder and 94 healthy control subjects. RESULTS: There was a significant association between TPH genotypes and manic-depressive illness. Among patients with bipolar disorder, no association was found between TPH alleles and suicidal behavior. CONCLUSIONS: This result suggests the involvement of the TPH gene in susceptibility to manic-depressive illness. This preliminary result requires confirmation in further groups of patients and controls.
Asunto(s)
Trastorno Bipolar/genética , Triptófano Hidroxilasa/genética , Adulto , Alelos , Trastorno Bipolar/enzimología , Trastorno Bipolar/psicología , Susceptibilidad a Enfermedades/enzimología , Femenino , Frecuencia de los Genes , Marcadores Genéticos , Genotipo , Humanos , Intrones , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Serotonina/biosíntesis , Suicidio/psicología , Intento de Suicidio/psicología , Intento de Suicidio/estadística & datos numéricos , Triptófano Hidroxilasa/fisiología , Violencia/psicologíaRESUMEN
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder displaying a large spectrum of symptoms. Linkage studies have shown two loci, TSC1 in 9q34 and TSC2 in 16p13.3, to be involved in the disease. The TSC2 gene, composed of 41 exons, has been isolated and is shown to encode a protein, tuberin, from a 5.5-kb transcript. Mutation screening for both clinical diagnosis and identification of functional domains within the tuberin is in progress. In this study we identify a 33-bp in-frame deletion (1462del33) in the mRNA which segregates in two unrelated French families with severe TSC phenotypes. The corresponding 11 amino acids deletion (aa 482-492) is shown to result from two different splice site mutations at exon 14 and, when compared with the position of two previously described missense mutations, indicates a novel functionally important region of the protein.
Asunto(s)
Empalme del ARN/genética , Proteínas Represoras/genética , Eliminación de Secuencia/genética , Esclerosis Tuberosa/genética , Secuencia de Aminoácidos , Análisis Mutacional de ADN , Exones/genética , Femenino , Francia , Heterogeneidad Genética , Humanos , Masculino , Linaje , Fenotipo , Polimorfismo Genético , Polimorfismo Conformacional Retorcido-Simple , ARN Mensajero/genética , Proteína 2 del Complejo de la Esclerosis Tuberosa , Proteínas Supresoras de TumorRESUMEN
The pathogenesis of schizophrenia might involve abnormal development of the human brain. Interleukin-1 beta is a cytokine implicated in the development of the central nervous system and therefore its gene is a candidate gene in schizophrenia. Polymorphisms within the coding sequence and the 3'UTR of the IL1 beta gene were searched for using PCR-SSCP. Two polymorphisms, 1B-175/1B-173 and 1B-1765/1B-1763 were found in addition to the previously published TaqI site. Furthermore, a mutant was found in codon 106 (exon 5) of the IL1 beta gene located next to the published polymorphism at the TaqI site and abolishing this site. This novel mutation encodes an Asp in place of an Asn and was only observed in one patient in our French population. Association studies were conducted with the polymorphisms 1B-175/1B-173 and TaqI. There was no allelic or genotypic association between either of the two polymorphisms and schizophrenia. In our population, there is no evidence that the IL1 beta gene is involved in schizophrenia.
Asunto(s)
Interleucina-1/genética , Polimorfismo Genético , Esquizofrenia/genética , Adulto , Alelos , Sustitución de Aminoácidos , Asparagina , Ácido Aspártico , Exones , Femenino , Francia , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Mutación Puntual , Reacción en Cadena de la Polimerasa , Polimorfismo Conformacional Retorcido-Simple , Mapeo Restrictivo , Esquizofrenia/inmunología , Eliminación de SecuenciaAsunto(s)
Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismo , Serotonina/metabolismo , Adulto , ADN/análisis , ADN/aislamiento & purificación , Femenino , Humanos , Linfocitos/química , Masculino , Repeticiones de Minisatélite , Polimorfismo Genético , Escalas de Valoración Psiquiátrica , Proteínas de Transporte de Serotonina en la Membrana PlasmáticaRESUMEN
Several studies have implicated the tyrosine hydroxylase (TH) locus within the 11p15 region in susceptibility to manic depressive illness (MDI). This possibility was further investigated by both parametric (lod score) and nonparametric (affected-pedigree-member and a case-control study) methods of analysis in 11 French MDI families and in a sample of 200 unrelated subjects. Both types of analyses corroborate the implication of this locus, and positive lod scores were obtained in two families, which most likely reflects genetic heterogeneity. Statistical analyses were also performed including available data from published reports. These analyses, which allowed for genetic heterogeneity, substantiated our findings. The combined maximum lod score for all the families studied was 3.68 at theta = 0.00 (number of families: 36) assuming heterogeneity (alpha = 15%, P = 0.01). Taken together these results converge to suggest that the risk factors for MDI lie in the 11p15 region with TH being the most likely candidate gene.
Asunto(s)
Trastorno Bipolar/genética , Heterogeneidad Genética , Ligamiento Genético , Tirosina 3-Monooxigenasa/genética , Alelos , Estudios de Casos y Controles , Salud de la Familia , Femenino , Genotipo , Humanos , Masculino , Linaje , Polimorfismo de Longitud del Fragmento de RestricciónRESUMEN
Pharmacological and clinical findings suggest that the dopamine transporter (DAT) gene may be involved in the genetic predisposition to schizophrenia. Linkage of a Taq I VNTR polymorphism in the DAT gene to schizophrenia was studied in multiplex schizophrenic families from Rouen, France (n = 10) and the Island of La Réunion (n = 21). Neither the lod score method nor nonparametric methods (the affected pedigree member method of Weeks and Lange [1988] and the sibling method of Green and Woodrow [1977]) provided any evidence for linkage. An association study, carried out within a group of 91 unrelated schizophrenic patients from Rouen and 91 matched control subjects, examined a 40 base-pair repeat polymorphism located in the 3' nontranslated end of the DAT mRNA. There was no significant difference in allelic or genotypic frequencies between the two groups. These results exclude any substantial involvement of the DAT gene in the pathogenesis of schizophrenia in the population studied.
Asunto(s)
Proteínas Portadoras/genética , Ligamiento Genético/genética , Glicoproteínas de Membrana , Proteínas de Transporte de Membrana , Proteínas del Tejido Nervioso , Esquizofrenia/genética , Adulto , Anciano , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Femenino , Francia , Genética de Población , Humanos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
We investigated the frequency of a rare variant of a common microsatellite tetrarepeat allele in the tyrosine hydroxylase gene in 2 independent ethnic groups of schizophrenic patients and their matched controls. In a French population we found the rare variant allele in 5 of 94 (5%) unrelated chronic schizophrenic patients and in none of 145 unaffected controls, thus yielding a significant association (p < 0.01) between schizophrenia and the tyrosine hydroxylase gene. Similarly, in a replication study, we found the rare allele in 4 of 44 (9%) unrelated chronic schizophrenic patients and in none of 44 unaffected controls in a Tunisian population. Albeit the reason of this association is at the moment unknown, it is possible that this polymorphism in the tyrosine hydroxylase gene may be involved in the regulation of its activity.
Asunto(s)
ADN Satélite/genética , Genes/genética , Secuencias Repetitivas de Ácidos Nucleicos , Esquizofrenia/genética , Tirosina 3-Monooxigenasa/genética , Adulto , Femenino , Francia , Humanos , Masculino , Esquizofrenia/etnología , TúnezAsunto(s)
Trastorno Bipolar/genética , Tirosina 3-Monooxigenasa/genética , Adulto , Biomarcadores , Trastorno Bipolar/enzimología , Femenino , Genotipo , Humanos , Intrones , MasculinoAsunto(s)
Cromosomas Humanos Par 3 , Receptores de Dopamina D2 , Receptores Dopaminérgicos/genética , Esquizofrenia/genética , Alelos , Estudios de Casos y Controles , Distribución de Chi-Cuadrado , Femenino , Frecuencia de los Genes , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Mutación Puntual , Receptores de Dopamina D3RESUMEN
A new structural polymorphism (Ser311/Cys311) in the dopamine D2 receptor (DRD2) gene has recently been reported to be associated with schizophrenia, particularly in patients with a positive family history of schizophrenia (Arinimi et al., 1994). However these findings remain controversial (Asherson et al., 1994; Nanko et al., 1994; Nöthen et al., 1994; Shaikh et al., 1994). Thus we investigated the role of the Cys311 mutation in schizophrenia using both association and family studies. First, we screened for the Cys311 mutation in 113 unrelated Caucasian schizophrenics (mean age 42 +/- 0.6; 34 females and 79 males) including 25 familial cases, and 184 unrelated controls (mean age 49 +/- 0.5, 74 females and 110 males) free of any psychiatric disorders. Diagnoses were ascertained according to DSM-III criteria (Campion et al., 1994). All patients and controls were native to the area of Rouen.
Asunto(s)
Mutación Puntual , Receptores de Dopamina D2/genética , Esquizofrenia/genética , Alelos , Cisteína , Femenino , Francia , Frecuencia de los Genes , Humanos , Masculino , Linaje , Serina , Población Blanca/genéticaRESUMEN
A single injection of reserpine causes a long lasting enhancement of the activity of tyrosine hydroxylase (TH), the enzyme catalyzing the rate-limiting step in the biosynthesis of catecholamines. A sensitive method has been developed to assay both TH mRNA level and enzyme activity in tissue from a single rat. The time course of the induction was analysed in adrenals, locus coeruleus and substantia nigra. In both locus coeruleus and adrenals reserpine caused respectively 4.2- and 4.5-fold increase of TH mRNA which was maximal 2 days after drug injection. This increase is about twice that of the enzyme activity. No change was observed in substantia nigra. The effect lasted longer in locus coeruleus than in adrenal. In the latter, TH mRNA had almost returned to initial values at day 4 whereas at this time it is 3-fold higher in locus coeruleus and still significant at day 18. This result suggests that induction of TH results from an enhanced transcription of the TH gene. The time course difference between locus coeruleus and adrenals is most likely to result from a difference in the stability of TH mRNA in the two structures.
Asunto(s)
Médula Suprarrenal/enzimología , Encéfalo/enzimología , ARN Mensajero/genética , Reserpina/farmacología , Tirosina 3-Monooxigenasa/genética , Médula Suprarrenal/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , ADN/metabolismo , Cinética , Masculino , Peso Molecular , Hibridación de Ácido Nucleico , ARN Mensajero/aislamiento & purificación , Ratas , Ratas Endogámicas , Factores de TiempoAsunto(s)
Médula Suprarrenal/enzimología , Encéfalo/enzimología , ARN Mensajero/genética , Tirosina 3-Monooxigenasa/genética , Neoplasias de las Glándulas Suprarrenales/enzimología , Médula Suprarrenal/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Línea Celular , Locus Coeruleus/enzimología , Masculino , Feocromocitoma/enzimología , Ratas , Ratas Endogámicas , Reserpina/farmacología , Sustancia Negra/enzimologíaRESUMEN
Five recombinant DNA plasmids have been constructed that contain structural gene sequences for rat tyrosine hydroxylase [TyrOHase; tyrosine 3-monooxygenase; L-tyrosine, tetrahydropteridine:oxygen oxidoreductase (3-hydroxylating), EC 1.14.16.2]. Rat pheochromocytoma PC 12 cell line, which contains relatively high levels of catecholamine-synthesizing enzymes, was used to purify RNA. TyrOHase cDNA clones were identified by screening 350 cDNA clones constructed from partially purified TyrOHase mRNA. A rapid and powerful screening of the recombinant clones by differential colony hybridization was possible because TyrOHase is a tissue-specific protein. The final selection relied on the ability of cDNA inserts to hybridize specifically to TyrOHase mRNA as judged by cell-free translation and immunoprecipitation. Blot hybridization analysis of polyadenylylated RNA from PC 12 cells indicated a major mRNA species of 1.9 kilobases. A species of the same size was identified from a human pheochromocytoma tumor, indicating a crossreactivity between rat TyrOHase cDNA and human TyrOHase mRNA.