Mutational analysis of the amyloid precursor protein gene in Japanese familial Alzheimer's disease kindreds.
ABSTRACT We sequenced the entire coding region of the amyloid precursor protein (APP) genes of 11 unrelated patients with Japanese familial Alzheimer's disease (FAD) in order to determine the exact frequency of known APP gene mutations and to search for novel mutations responsible for FAD. Three out of 11 (27.3%) FAD patients showed the known Val to Ile mis-sense mutation at codon 717, but no other mutations were detected in the entire coding region. Analysis of exons 16 and 17 in 30 Japanese with sporadic AD revealed no mutations. Moreover, there were no significant differences in the allele frequencies of the DNA polymorphism in intron 9 among the 11 FAD, 39 sporadic AD, and 110 control subjects.
Article: No founder effect in three novel Alzheimer's disease families with APP 717 Val-->Ile mutation. Clerget-darpoux. French Alzheimer's Disease Study Group.[show abstract] [hide abstract]
ABSTRACT: We sequenced exons 16 and 17 of the APP (amyloid precursor protein) gene in 18 unrelated French Alzheimer's disease (AD) patients. These patients had an onset before the age of 60 and belonged to families with autosomal dominant transmission of the disease. We detected the APP 717 Val-->Ile mutation in three out of 18 (16.6%) families. In these three families, all affected subjects had the APOE 3/3 genotype, but their ages of onset ranged from 38 to 60 years, indicating that factors other than the APOE genotype influence age of onset. Analysis of two polymorphic loci adjacent to the APP gene showed that at least two independent mutational events had occurred within these pedigrees, in spite of their origin in the same region of France.Journal of Medical Genetics 09/1996; 33(8):661-4. · 6.36 Impact Factor
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ABSTRACT: Two sisters with familial Alzheimer's disease developed spastic gait disturbance as an initial manifestation. Their gait disturbance progressed gradually, followed by dementia a few years later. Post-mortem examination of one of the patients disclosed degeneration of the thalamus and corticospinal tract in addition to numerous senile plaques and neurofibrillary tangles in the neocortex, both of which were confirmed by immunohistochemistry. This is the first report in which clinicopathological evaluation is sufficient to establish a new variant of Alzheimer's disease presenting initially as spastic tetraplegia.Journal of Neurology Neurosurgery & Psychiatry 11/1995; 59(4):395-9. · 4.76 Impact Factor
Article: PuF, an antimetastatic and developmental signaling protein, interacts with the Alzheimer's amyloid-beta precursor protein via a tissue-specific proximal regulatory element (PRE).[show abstract] [hide abstract]
ABSTRACT: BACKGROUND: Alzheimer's disease (AD) is intimately tied to amyloid-beta (Abeta) peptide. Extraneuronal brain plaques consisting primarily of Abeta aggregates are a hallmark of AD. Intraneuronal Abeta subunits are strongly implicated in disease progression. Protein sequence mutations of the Abeta precursor protein (APP) account for a small proportion of AD cases, suggesting that regulation of the associated gene (APP) may play a more important role in AD etiology. The APP promoter possesses a novel 30 nucleotide sequence, or "proximal regulatory element" (PRE), at -76/-47, from the +1 transcription start site that confers cell type specificity. This PRE contains sequences that make it vulnerable to epigenetic modification and may present a viable target for drug studies. We examined PRE-nuclear protein interaction by gel electrophoretic mobility shift assay (EMSA) and PRE mutant EMSA. This was followed by functional studies of PRE mutant/reporter gene fusion clones. RESULTS: EMSA probed with the PRE showed DNA-protein interaction in multiple nuclear extracts and in human brain tissue nuclear extract in a tissue-type specific manner. We identified transcription factors that are likely to bind the PRE, using competition gel shift and gel supershift: Activator protein 2 (AP2), nm23 nucleoside diphosphate kinase/metastatic inhibitory protein (PuF), and specificity protein 1 (SP1). These sites crossed a known single nucleotide polymorphism (SNP). EMSA with PRE mutants and promoter/reporter clone transfection analysis further implicated PuF in cells and extracts. Functional assays of mutant/reporter clone transfections were evaluated by ELISA of reporter protein levels. EMSA and ELISA results correlated by meta-analysis. CONCLUSIONS: We propose that PuF may regulate the APP gene promoter and that AD risk may be increased by interference with PuF regulation at the PRE. PuF is targeted by calcium/calmodulin-dependent protein kinase II inhibitor 1, which also interacts with the integrins. These proteins are connected to vital cellular and neurological functions. In addition, the transcription factor PuF is a known inhibitor of metastasis and regulates cell growth during development. Given that APP is a known cell adhesion protein and ferroxidase, this suggests biochemical links among cell signaling, the cell cycle, iron metabolism in cancer, and AD in the context of overall aging.BMC Genomics 01/2013; 14(1):68. · 4.07 Impact Factor