A polymorphic microsatellite repeat within the ECE-1c promoter is involved in transcriptional start site determination, human evolution, and Alzheimer's disease.
J Neurosci
; 32(47): 16807-20, 2012 Nov 21.
Article
em En
| MEDLINE
| ID: mdl-23175834
ABSTRACT
Genetic factors strongly contribute to the pathogenesis of sporadic Alzheimer's disease (AD). Nevertheless, genome-wide association studies only yielded single nucleotide polymorphism loci of moderate importance. In contrast, microsatellite repeats are functionally less characterized structures within our genomes. Previous work has shown that endothelin-converting enzyme-1 (ECE-1) is able to reduce amyloid ß content. Here we demonstrate that a CpG-CA repeat within the human ECE-1c promoter is highly polymorphic, harbors transcriptional start sites, is able to recruit the transcription factors poly(ADP-ribose) polymerase-1 and splicing factor proline and glutamine-rich, and is functional regarding haplotype-specific promoter activity. Furthermore, genotyping of 403 AD patients and 444 controls for CpG-CA repeat length indicated shifted allelic frequency distributions. Sequencing of 245 haplotype clones demonstrated that the overall CpG-CA repeat composition of AD patients and controls is distinct. Finally, we show that human and chimpanzee [CpG](m)-[CA](n) ECE-1c promoter repeats are genetically and functionally distinct. Our data indicate that a short genomic repeat structure constitutes a novel core promoter element, coincides with human evolution, and contributes to the pathogenesis of AD.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Transcrição Gênica
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Metaloendopeptidases
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Ácido Aspártico Endopeptidases
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Regiões Promotoras Genéticas
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Repetições de Microssatélites
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Evolução Biológica
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Doença de Alzheimer
Limite:
Animals
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Humans
Idioma:
En
Revista:
J Neurosci
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Alemanha