Somatic mutational analyses of the APP and Presenillin 1 genes in Alzheimer's disease patients brains using Denaturing Gradient Gel Electrophoresis (DGGE).
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- 作者：Reznik-Wolf ; Haike ; Machado ; Joao ; Haroutunlan ; Vahram ; DeMarco ; Luiz ; Walter ; Gerhard Franz ; et. al.
- 刊名：Neurobiology of Aging
- 出版年：1996
- 出版时间：1996
- 年：1996
- 卷：17
- 期：4, Supplement 1
- 页码：S14
- 全文大小：117 K
文摘
The molecular basis for sporadic Alzheimer's disease (AD) remains largely unknown, despite the demonstration of linkage to several distinct chromosomal regions in early onset AD. In a subset of early onset AD patients, germline mutations in exons 16 and 17 of the Amyloid Precursor Protein (APP) gene and mutations within the presenillin 1 (S182) gene have been demonstrated. We hypothesized that in some cases of sporadic, late onset AD, a somatic mutation in an embryonic cell committed to neuronal development within the APP or the presenillin 1 genes may result in AD phenotype. A precedent for a somatic, mosaic pattern of mutations has been demonstrated within the Gs Alpha gene in affected tissues of patients with McCune Albright syndrome. Using PCR and DGGE complemented by direct DNA sequencing of the PCR products, we analyzed exons 16 and 17 of the APP gene in 99 paraffin embedded and fresh brain tissues from patients with histopathologically proven AD. As a positive control, we used a germline mutation from a Swedish family with a germline mutation in exon 16. No migration abnormalities were demonstrated in any sample in either exon, whereas the known mutation was easily detected as an abnormally migrating band. Sequence analysis of exons 16 and 17 in two samples did not reveal any sequence alterations. One known mutation within the S182 gene was demonstrated by restriction enzyme digest (His163Arg) and a novel mutation (Glu120Asp) was additionally detected in a familial case. We are currently analyzing more brains to evaluate our working hypothesis utilizing a more comprehensive approach to mutation detection within the S182 gene, and up-to-date results will be presented.