RESUMEN
Type 2 diabetes (T2D) is a common, polygenic chronic disease with high heritability. The purpose of this whole-genome association study was to discover novel T2D-associated genes. We genotyped 500 familial cases and 497 controls with >300,000 HapMap-derived tagging single-nucleotide-polymorphism (SNP) markers. When a stringent statistical correction for multiple testing was used, the only significant SNP was at TCF7L2, which has already been discovered and confirmed as a T2D-susceptibility gene. For a replication study, we selected 10 SNPs in six chromosomal regions with the strongest association (singly or as part of a haplotype) for retesting in an independent case-control set including 2,573 T2D cases and 2,776 controls. The most significant replicated result was found at the AHI1-LOC441171 gene region.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Frecuencia de los Genes , Desequilibrio de Ligamiento , Polimorfismo de Nucleótido Simple , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras del Transporte Vesicular , Estudios de Casos y Controles , Inglaterra , Femenino , Finlandia , Predisposición Genética a la Enfermedad , Genoma Humano , Alemania , Humanos , Israel , Judíos/genética , Masculino , Población BlancaRESUMEN
Diazepam binding inhibitor (DBI) and its processing products are endogenous modulators of GABAA and linked to various brain disorders ranging from anxiety and drug dependence to epilepsy. To investigate the physiological role of endogenously expressed DBI in the brain we created a transgenic mouse line overexpressing DBI gene. Transgenic mice had a 37x increased protein expression and immunohistochemistry showed excessive glial expression in the infragranular region of the dentate gyrus. Transgenic animals had significantly larger lateral ventricles and decreased plasticity of excitatory synapses without affecting either inhibitory or excitatory synaptic transmission. In behavioral tests transgenic animals had no differences in motor and exploratory activity, yet impaired hippocampus-dependent learning and memory. Overexpression did not cause anxiety or proconflict behavior, nor influenced kainic acid or pentylenetetrazole induced seizure activity. Our transgenic mouse line demonstrates that endogenously overexpressed DBI impairs hippocampus-dependent learning without anxiety or proconflict behavior.
Asunto(s)
Inhibidor de la Unión a Diazepam/metabolismo , Hipocampo/fisiopatología , Hidrocefalia/etiología , Discapacidades para el Aprendizaje/genética , Potenciación a Largo Plazo/genética , Transmisión Sináptica/genética , Animales , Reacción de Prevención/fisiología , Conducta Animal , Femenino , Hidrocefalia/genética , Hidrocefalia/patología , Discapacidades para el Aprendizaje/patología , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Transgénicos , Fosfopiruvato Hidratasa/metabolismo , Tiempo de Reacción/genéticaRESUMEN
We have generated mouse embryonic stem cells with targeted disruption of spermidine/spermine N(1)-acetyltransferase (SSAT) gene. The targeted cells did not contain any inducible SSAT activity, and the SSAT protein was not present. The SSAT-deficient cells proliferated normally and appeared to maintain otherwise similar polyamine pools as did the wild-type cells, with the possible exception of constantly elevated (about 30%) cellular spermidine. As expected, the mutated cells were significantly more resistant toward the growth-inhibitory action of polyamine analogues, such as N(1),N(11)-diethylnorspermine. However, this resistance was not directly attributable to cellular depletion of the higher polyamines spermidine and spermine, as the analogue depleted the polyamine pools almost equally effectively in both wild-type and SSAT-deficient cells. Tracer experiments with [C(14)]-labeled spermidine revealed that SSAT activity is essential for the back-conversion of spermidine to putrescine as radioactive N(1)-acetylspermidine and putrescine were readily detectable in N(1),N(11)-diethylnorspermine-exposed wild-type cells but not in SSAT-deficient cells. Similar experiments with [C(14)]spermine indicated that the latter polyamine was converted to spermidine in both cell lines and, unexpectedly, more effectively in the targeted cells than in the parental cells. This back-conversion was only partly inhibited by MDL72527, an inhibitor of polyamine oxidase. These results indicated that SSAT does not play a major role in the maintenance of polyamine homeostasis, and the toxicity exerted by polyamine analogues is largely not based on SSAT-induced depletion of the natural polyamines. Moreover, embryonic stem cells appear to operate an SSAT-independent system for the back-conversion of spermine to spermidine.
Asunto(s)
Acetiltransferasas/metabolismo , Poliaminas Biogénicas/metabolismo , Embrión de Mamíferos/citología , Homeostasis , Células Madre/enzimología , Acetiltransferasas/genética , Animales , Secuencia de Bases , Cartilla de ADN , RatonesRESUMEN
A large number of studies applying inhibitors of polyamine biosynthesis have indicated that these compounds are required for animal cell proliferation. Here we show, using a transgenic rat model with activated polyamine catabolism, that a certain critical concentration of the higher polyamines spermidine and spermine is required for liver regeneration. Partial hepatectomy of transgenic rats expressing spermidine/spermine N(1)-acetyltransferase (SSAT) under the control of mouse metallothionein promoter strikingly induced the enzyme at 24 h and reduced hepatic spermidine by 80%. At that time, the weight of the liver remnant was significantly increased in syngenic rats and proliferating cell nuclear antigen (PCNA) labelling index was 20%, whereas the transgenic rats showed no liver weight gain and their PCNA-positive cells accounted for 0.5% of hepatocytes. Similarly, hepatic thymidine incorporation was markedly enhanced at this time point in syngenic, but not in transgenic, animals, whereas the rate of leucine incorporation was only marginally affected in the transgenic animals. At 3 days after operation, the spermidine pool in transgenic livers had increased to the pre-operative level, the remnant weight was significantly elevated and hepatic PCNA labelling index increased to 5%. N(1),N(11)-Diethylnorspermine, a powerful inducer of SSAT, inhibited liver weight gain and proliferative activity in both syngenic and transgenic rats. We found an extremely close correlation between hepatic spermidine, and less close between spermine, concentrations and PCNA labelling index during early liver regeneration. These results indicate that spermidine and/or spermine, but apparently not putrescine, are required for liver regeneration, yet at concentrations smaller than those normally found after partial hepatectomy.