Analysis On The Genetics In Familial Alzheimer's Disease

Background:Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory impairment and multiple cognitive deficits. It is defined by the pathological hallmarks of senile plaques and neurofibrillary tangles in the cerebral cortex accompanied by neuronal loss. With the development of molecular genetics,there are four genetic loci now known to be related to the etiology of familial Alzheimer's disease (FAD):presenilin 1(PS-1) gene, presenilin 2{PS-2) gene, the amyloid precursor protein (APP) gene and the tau gene.Mutations in the PS-1 gene are by far the most common among the four genes associated with FAD.So far,176 mutations in PS-1 have been reported in 390 families.(http://www.molgen.ua.ac.be/AD Mutations/). We analyze mutations of these four genes in two AD families.Objective:To analyze the genetics in familial Alzheimer's disease (FAD).Methods:By technology of polymerase chain reaction(PCR),direct DNA sequencing and restriction enzyme digestion,mutation analysis of PS-1 gene, PS-2 gene, APP gene and the tau gene in one family wih EOFAD and the other family wih LOFAD was performed. Then, mutation analysis was performed again of those genes with allele changes in 100 controls to decide whether they were mutations or polymorphism. Results:Molecular genetic analysis showed a novel 3 bp ATC deletion in one allele at nucleotide 507-509 of the coding DNA of PS-lin the first family,which results in the deletion of serine in codon 169(Serl69del). We found the novel changes(Ser169del) was present in the two patients, but not in normal population,the novel change mighet be a pathogenic mutation.Sequencing revealed that a synonymous mutation (T69C) in coding region of exon 1 of PS-2 gene and two non-coding nucleotide changes were found in the proband of the other familiy, but not found in another patient of this family.The results indicated that these three changes were not pathogenic mutations. Two EOF AD patients in the family with Serl69del had a clinical phenotype with a early-onset (mean age of onset was 43),progressive memory decline,cognitive dysfunction,and so on.Conclusions:We first report a novel mutation (Serl69del) of the PS-1 gene,The mutation might be one of the causative factors in EOFAD.