Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3

Abstract

Genetic linkage studies have indicated that chromosome 14q24.3 harbours a major locus for early-onset (onset age <65 years) Alzheimer's disease (AD3). Positional cloning efforts have identified a novel gene S182 or presenilin 1 as the AD3 gene. We have mapped S182 in the AD3 candidate region between D14S277 and D14S284 defined by genetic linkage studies in the two chromosome 14 linked, early-onset AD families AD/A and AD/B. We have shown that S182 is expressed in lymphoblasts and have determined the complete cDNA in both brain and lymphoblasts by RT-PCR sequencing. S182 is alternatively spliced in both brain and lymphoblasts within a putative phosphorylation site located 5' in the coding region. We identified two novel mutations, Ile143Thr and Gly384la located in, respectively, the second transmembrane domain and in the sixth hydrophilic loop of the putative transmembrane structure of S182. As families AD/A and AD/B have very similar AD phenotype our observation of two mutations in functionally different domains suggest that onset age and severity of AD may not be very helpful predictors of the location of putative S182 mutations.

The PSEN1 I143T mutation in a Swedish family with Alzheimer's disease: clinical report and quantification of Aβ in different brain regions

“…This mutation has previously been reported to cause EOAD both in single unrelated cases, related cases and in two families in which segregation was proven, but clinical, neuropathological, and biochemical details have been lacking. [16][17][18][19][20][21][22][23] The form of EOAD recurring in this family is severe and its mean onset age is reported to be 34 years, whereas the mean age of death is 41.2 years (http://www.molgen.ua.ac.be/ADMutations). Our clinical investigation revealed an aggressive form of AD with rapid progression and extensive myoclonia.…”

Alzheimer's presenilin 1 gene expression in platelets and megakaryocytes

“…The importance of these isoforms should be considered since the sequence VRSQ (VRXQ motif) may be part of two potential phosphorylation sites for casein kinase II and protein kinase C in the PSI molecule [7]. Both isoforms are present in almost equimolecular amounts in platelets, megakaryocytes and neural cell lines whereas brain and lymphoblasts have a different pattern with the shorter isoform representing more than 60% ( [24] and unpublished observation). A shorter mRNA derived by alternative splicing of exon 8 (codons 257-289) is present in low amounts in both platelets and megakaryocytes.…”

Splicing mutation of presenilin-1 gene for early-onset familial Alzheimer's disease

“…Van Broeckhoven C (1995) by Perez-Tur et al (Neuro report 7:297-301, 1995) in which the intron9 acceptor site sequence AG is mutated at AT.…”

“…From those structural features, PS-1 and PS-2 are predicted to be a receptor or channel protein, while it remains to be elucidated. So far at least 20 different mutations of PS-I for EOFAD have been identified (Alzheimer's Disease Collaborative Group, 1995;Boteva et al, 1996;Campion et al, 1995;Cruts et al, 1995;Rogaev et al, 1995;Sherrington et al, 1995;Sorbi et al, 1995;Tanahashi et al, 1995;Van Broeckhoven 1995;Wasco et al, 1995). All were missense mutations that cause single amino acid substitutions at the residues conserved between PS-1 and PS-2.…”