RESUMO
A common intronic single nucleotide polymorphism (T102C) in the 5-HT2A receptor gene is associated with the development of different neuropsychiatric symptoms, including hallucinations and depressive symptoms in Alzheimer's disease (AD). Differential 5-HT2A receptor binding has also been associated with the development of these symptoms in AD. However, the relationship between 5-HT2A (T102C) genotype and 5-HT2A receptor binding in AD and control human brains has not been examined. We examined the association between different 5-HT2A (T102C) genotypes and [(3)H] ketanserin binding in the temporal and frontal cortex of 20 AD and 14 control human brains. In homozygotes, but not heterozygotes, there was a significant reduction in B(max) values for [(3)H] ketanserin binding in both areas of cortex in AD compared with control subjects. This study suggests a mechanism for the generation of different neuropsychiatric symptoms in AD from a single nucleotide polymorphism with reduced receptor binding in T102C 5-HT2A receptor gene homozygotes correlating with susceptibility to depressive symptoms, whereas the relative preservation of receptor binding in heterozygotes with AD correlating with susceptibility to hallucinations.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Ketanserina/metabolismo , Neocórtex/metabolismo , Receptor 5-HT2A de Serotonina/genética , Receptor 5-HT2A de Serotonina/metabolismo , Antagonistas da Serotonina/metabolismo , Idoso , Doença de Alzheimer/psicologia , Feminino , Variação Genética , Genótipo , Alucinações/etiologia , Alucinações/genética , Alucinações/psicologia , Humanos , Técnicas In Vitro , Cinética , Masculino , Polimorfismo de Nucleotídeo Único , Córtex Pré-Frontal/metabolismo , Lobo Temporal/metabolismoRESUMO
OBJECTIVE: To determine whether individuals with Alzheimer's disease (AD) and the K variant allele of butyrylcholinesterase have a slower rate of cognitive decline than those without the K variant allele of butyrylcholinesterase. METHOD: The cognitive status of 339 community based subjects with AD was assessed with the Mini Mental State Examination at baseline and yearly over a three year follow up period. The rates of cognitive decline of subjects with and without the K variant allele were compared. RESULT: Presence of the K allele was associated with a slower average rate of cognitive decline in subjects with severe AD. CONCLUSIONS: This finding is consistent with the suggestion that the K variant of butyrylcholinesterase has an important role in disease progression in AD, and this may have implications for treatment.
Assuntos
Doença de Alzheimer/enzimologia , Butirilcolinesterase/genética , Transtornos Cognitivos/etiologia , Idoso , Idoso de 80 Anos ou mais , Alelos , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Transtornos Cognitivos/diagnóstico , Estudos de Coortes , Demografia , Feminino , Variação Genética , Genótipo , Humanos , Masculino , Testes NeuropsicológicosRESUMO
The transcription map of the human genome published by Schuler et al. (1996) is a valuable resource in which approximately one quarter of all human genes have been mapped with respect to genetic framework markers using radiation hybrids. We have taken information from this map to provide potential genes within the TSC1 candidate region on chromosome 9q34. In so doing we have been able to provide an independent assay of the quality of the radiation hybrid mapping by using somatic cell hybrids and a 2 Mb cosmid contig covering the TSC1 region as mapping tools. In addition, we have built sequence contigs of ESTs for 25 clusters. This has shown that about 20% of the relevant EST clusters in the Unigene resource (Boguski & Schuler 1995) contain chimaeric clones.
