MOLECULAR ANALYSIS OF THE PRESENILIN-1 (S182) GENE IN SPORADIC CASES OF ALZHEIMERS-DISEASE - IDENTIFICATION AND CHARACTERIZATION OF UNUSUALSPLICE VARIANTS

Mutations of the presenilin 1 (PS-1) gene at the Alzheimer's disease ( AD) FAD3 locus on chromosome 14q24.3 are responsible for the majority of familial early-onset AD. As genes responsible for familial forms of AD are obvious candidates for further investigation in ''sporadic'' d isease, we performed a molecular analysis of PS-1 transcripts extracte d from brain tissues of a series of histologically confirmed cases of ''sporadic'' AD (n = 10) and also from histologically ''normal'' (non- Alzheimer) age-matched brain controls (n = 5). No sequence changes in the PS-1 coding sequence were detected after analysis by reverse trans cription-PCR. This suggests that the frequency of mutations in the PS- 1 (S182) coding region in ''sporadic'' Alzheimer's disease is very low . However, we demonstrated that the PS-1 gene is highly variably splic ed. One splice variant involves the 5' untranslated region of the PS-1 gene only and hence encodes for normal PS-1. Six further splice varia nts involve coding regions of the PS-1 gene and result in truncated pr oteins lacking specific transmembrane domains. Most of these variants do not coincide with recognized sites of introns in the PS-I gene. One of these variants, resulting in the loss of transmembrane domain TM-V II, was found only in an AD patient.