RESUMEN
Bipolar affective disorder (BPAD) is a common psychiatric disorder with complex genetic aetiology. We have undertaken a genome-wide scan in one of the largest samples of bipolar affected sibling pairs (ASPs) using a two-stage approach combining sample splitting and marker grid tightening. In this second stage analysis, we have examined 17 regions that achieved a nominally significant maximum likelihood LOD score (MLS) threshold of 0.74 (or 1.18 for the X-chromosome) in stage one. The second stage has added 135 ASP families to bring the total stage 2 sample to 395 ASPs. In total, 494 microsatellite markers have been used to screen the human genome at a density of 10 cM in the first stage sample (260 ASPs) and 5 cM in the second stage. Under the broad diagnostic model, two markers gave LOD scores exceeding 3 with two-point analysis: D4S392 (LOD=3.30) and D10S197 (LOD=3.18). Multipoint analysis demonstrated suggestive evidence of linkage between BPAD and chromosomal regions 6q16-q21 (MLS=2.61) and 4q12-q21 (MLS=2.38). 6q16-q21 is of particular interest because our data, together with those from two recent genome scans, make this the best supported linkage region in BPAD. Further, our data show evidence of a gender effect at this locus with increased sharing predominantly within the male-male pairs. Our scan also provides support for linkage (MLS> or =1.5) at several other regions that have been implicated in meta-analyses of bipolar disorder and/or schizophrenia including 9p21, 10p14-p12 and 18q22.
Asunto(s)
Trastorno Bipolar/genética , Cromosomas Humanos Par 10 , Cromosomas Humanos Par 18 , Cromosomas Humanos Par 4 , Cromosomas Humanos Par 6 , Cromosomas Humanos Par 9 , Mapeo Cromosómico , Femenino , Marcadores Genéticos , Pruebas Genéticas , Genoma Humano , Humanos , Escala de Lod , Masculino , Padres , Linaje , HermanosRESUMEN
We have completed the first stage of a two-stage genome wide screen designed to identify chromosomal regions that may harbour susceptibility genes for bipolar affective disorder. The first stage screening sample included 509 subjects from 151 nuclear families recruited within the United Kingdom and Republic of Ireland. This sample contained 154 narrowly defined affected sibling pairs (DSM-IV BPI) and 258 broadly defined affected sibling pairs (DSM-IV BPI, SABP, BPII, BPNOS or MDD(R)), approximately two thirds of all families contained at least one other additional typed individual. All individuals were genotyped using 398 highly polymorphic microsatellite markers from Applied Biosystems's Linkage Mapping Set Version 2. The average inter-marker distance was 9.6 cM and the mean heterozygosity was 0.78. Analysis of these data using non-parametric linkage methods (MAPMAKER/SIBS) found no evidence for loci of major effect and no regions reached genome-wide significance for either suggestive or significant linkage. We identified 19 points across the genome where the MLS exceeded a value set for follow up in our second stage screen (MLS > or = 0.74 (equivalent to a nominal pointwise significance of 5%) under the narrowest diagnostic model). These points were on chromosomes 2, 3, 4, 6, 7, 9, 10, 12, 17, 18 & X. Some of these points overlapped with previous linkage reports both within bipolar affective disorder and other psychiatric illnesses. Under the narrowest diagnostic model, the single most significant multipoint linkage was on chromosome 18 at marker D18S452 (MLS=1.54). Overall the highest MLS was 1.70 on chromosome 2 at marker D2S125, under the broadest diagnostic model.
Asunto(s)
Trastorno Bipolar/genética , Escala de Lod , Adulto , Mapeo Cromosómico , Salud de la Familia , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Genotipo , Humanos , Irlanda , Repeticiones de Microsatélite , Persona de Mediana Edad , Núcleo Familiar , Reino UnidoRESUMEN
gamma-Glutamylcysteine synthetase (GCS), the rate-limiting enzyme in the de novo synthesis of GSH, is a heterodimer, consisting of a catalytic (GCSh) and a regulatory subunit (GCSl). We previously demonstrated that the constitutive and beta-naphthoflavone (beta-NF)-induced expression of the GCSh gene is mediated by a distal antioxidant response element (ARE), ARE4, located 3.1 kb upstream of the transcriptional start site [Mulcahy, Wartman, Bailey and Gipp (1997) J. Biol. Chem. 272, 7445-7454]. ARE4 consists of a consensus ARE sequence (5'-GTGACTCAGCG-3') containing an embedded PMA-responsive element (TRE, underlined). The relative significance of the two overlapping response elements to constitutive and beta-NF-induced expression of the GCSh gene was determined by mutational analyses. The internal activator protein-1 (AP-1)-binding sequence mediated constitutive expression of promoter/reporter transgenes, but was not required for beta-NF responsiveness. In gel-shift experiments, the TRE was necessary for binding of proteins from nuclear extracts prepared from untreated HepG2 cells. In contrast, induction by beta-NF was dependent on an intact ARE sequence, particularly the terminal GC box of ARE4. The GC box of ARE4 was shown to be essential for both basal and beta-NF-induced expression of reporter constructs. This element also influenced binding of nuclear proteins to ARE4, specifically in extracts isolated from beta-NF-treated HepG2 cells. Because previous studies indicated that ARE4 may co-operate with a separate putative ARE, the role of the neighbouring sequence (ARE3), located 34 bases downstream of ARE4, was also evaluated. Mutation of this element within a GCSh promoter/reporter did not modify the basal or beta-NF-induced expression of the transgene, demonstrating that ARE3 does not influence the constitutive or beta-NF-induced expression of the GCSh gene.
Asunto(s)
Antioxidantes/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Glutamato-Cisteína Ligasa/genética , beta-naftoflavona/farmacología , Sitios de Unión/fisiología , Análisis Mutacional de ADN , Elementos de Facilitación Genéticos/genética , Genes Sobrepuestos , Humanos , Hígado/enzimología , Proteínas Nucleares/análisis , Oligodesoxirribonucleótidos/genética , Regiones Promotoras Genéticas/genética , ARN Mensajero/metabolismo , Acetato de Tetradecanoilforbol/farmacología , Factor de Transcripción AP-1/farmacología , Células Tumorales CultivadasAsunto(s)
Poliposis Adenomatosa del Colon/genética , Proteínas del Citoesqueleto/genética , Mutación de Línea Germinal , Proteína de la Poliposis Adenomatosa del Colon , Secuencia de Bases , Codón de Terminación/genética , ADN/química , ADN/genética , Análisis Mutacional de ADN , Salud de la Familia , Mutación del Sistema de Lectura , Humanos , Irlanda , Mutagénesis Insercional , Mutación Puntual , Polimorfismo Conformacional Retorcido-Simple , Eliminación de SecuenciaRESUMEN
Achalasia of the esophagus developed in two male siblings soon after birth, and they were successfully treated by surgery. Persistent signs resulted in the later diagnosis of Hirschsprung's disease. One required subtotal colectomy and ileoanal anastomosis, and the other is managing well on conservative treatment. Genetic analysis of the genes encoding the RET protooncogene, endothelin-3, and the endothelin-3 receptor did not show any defect. Familial achalasia of the esophagus in combination with Hirschsprung's disease has never been reported.
Asunto(s)
Acalasia del Esófago/complicaciones , Acalasia del Esófago/genética , Enfermedad de Hirschsprung/complicaciones , Enfermedad de Hirschsprung/genética , Colectomía , Acalasia del Esófago/cirugía , Fundoplicación , Enfermedad de Hirschsprung/cirugía , Humanos , Lactante , Masculino , Proctocolectomía RestauradoraAsunto(s)
Poliposis Adenomatosa del Colon/genética , Genes APC , Mutación , Cartilla de ADN , ADN de Cadena Simple , Exones , Femenino , Humanos , Irlanda , Masculino , Conformación de Ácido Nucleico , LinajeRESUMEN
A comparison was performed of three small-gauge, permanent, rare-earth, intraocular magnets to assist the posterior segment surgeon with the decision as to which magnet to purchase or to use in different clinical situations. The magnetic force was measured at varying distances from the instrument tip using a 1/8-inch steel ball as the test object. There were small differences in magnetic strength between the three instruments that may have clinical significance in certain situations. Two of the instruments had a retractable magnet within an outer sleeve, allowing for controlled attraction and release of a magnetic foreign body by the surgeon.