Susanne Froelich

A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene

A series of mutations has been reported in the presenilin-1 (PS-1) gene which cause early onset Alzheimers disease (AD). The mutations reported to date have encoded missense mutations which alter residues conserved between PS-1 and the presenilin-2 (PS-2) gene. We have recently determined the intron/exon structure of the PS-1 gene and this information has been used to identify a mutation in the splice acceptor site for exon 9 in a family with early onset AD. Amplification of cDNA from lymphoblasts of affected individuals revealed that the effect of the mutation was to cause splicing out of exon 9, however it does not change the open reading frame of the mRNA. The importance of this observation is discussed.

Mapping of a disease locus for familial rapidly progressive frontotemporal dementia to chromosome 17q12-21

Familial frontotemporal dementia (FTD) is a complex disorder with lack of distinctive histopathological markers found in other types of dementia. Most of the linkage reports from FTD families map the disease loci to chromosome 17q21-22. However, FTD is genetically heterogeneous, as linkage also has been reported to chromosome 3. In the present study, we investigated the genetics of a Swedish family with an early-onset type of rapidly progressive FTD, associated with muscular rigidity and akinetic movements. Neuropathological features such as severe frontal lobe degeneration, spongy changes, and gliosis were present in affected family members. We here report probable linkage to chromosome 17q12-21 with a maximum two-point lod score of 2.76 at theta = 0 for marker D17S806, and a peak multipoint lod score of 2.86 for the same marker. Linkage to chromosome 3 was excluded, as two-point lod scores of -2.79, and -2.27 at theta = 0.01 for markers D3S1603 and D3S1552, respectively, were obtained. Sequencing of the translated exons of a strong candidate gene in the linked region of chromosome 17, the tau gene, failed to identify any mutations segregating with the disease.

A novel pathogenic mutation (Leu262Phe) found in the presenilin 1 gene in early-onset Alzheimer's disease

Several mutations causing early-onset familial Alzheimers disease (AD) have been detected in the presenilin 1 (PS-1) gene. Pathogenic mutations have also been described in an homologous gene, presenilin 2 (PS-2). In order to screen for mutations in these genes, cDNA samples from early-onset AD cases were analysed, using single strand conformation polymorphism (SSCP) and direct cDNA sequencing. Two missense mutations in the PS-1 gene were detected, a previously unidentified amino acid substitution Leu262Phe and an earlier reported amino acid substitution Glu318Gly. No disease-related mutations were found in the PS-2 gene.

Quantification of presenilin-1 mRNA in Alzheimer's disease brains

The presenilin‐1 (PS‐1) gene on chromosome 14 carries mutations which cosegregate with early‐onset familial Alzheimers disease. We quantified PS‐1 mRNA in post‐mortem mid‐temporal and superior frontal cortices from 14 Alzheimers disease subjects, 9 non‐demented controls and 5 subjects with other neurological diseases using solution hybridisation‐RNase protection assay. APP and APLP2 mRNAs had previously been quantified in these samples (Johnston et al. (1996) Mol. Brain Res., in press) and subjects were apolipoprotein E (APOE) genotyped. There were no significant differences between PS‐1 mRNA levels per pg total RNA in mid‐temporal or superior frontal cortices of the Alzheimers disease subjects, compared to controls. PS‐1 mRNA levels corresponded to 10% of total APP and 30% of APLP2 mRNA levels, and were not significantly affected by age, post‐mortem delay, tissue pH, or APOE genotype. PS‐1 mRNA showed significant positive correlations with APP and APLP2 mRNA levels in mid‐temporal cortex and with APP mRNA in superior frontal cortex. This may reflect a co‐regulation of the expression of these genes, or the fact that they are expressed in similar neuronal populations.