Missense mutations in the presenilin 2 (PS-2) gene on chromosome 1 were sought by direct nucleotide sequence analysis of the open reading frame of 60 pedigrees with familial Alzheimer's disease (FAD). In the majority of these pedigrees, PS-1 and β-amyloid precursor protein (βAPP) gene mutations had been excluded. While no additional PS-2 pathogenic mutations were detected, four silent nucleotide substitutions and alternative splicing of nucleotides 1338-1340 (Glu325) were observed. Analysis of additional members of a pedigree known to segregate a Met239Val mutation in PS-2 revealed that the age of onset of symptoms is highly variable (range 45-88 years). This variability is not attributable to differences in ApoE genotypes. These results suggest (i) that, in contrast to mutations in PS-1, mutations in PS-2 are a relatively rare cause of FAD; (ii) that other genetic or environmental factors modify the AD phenotype associated with PS-2 mutations; and (iii) that still other FAD susceptibility genes remain to be identified.
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Sherrington, R., Froelich, S., Sorbi, S., Campion, D., Chi, H., Rogaeva, E. A., … St George-Hyslop, P. H. (1996). Alzheimer’s disease associated with mutations in presenilin 2 is rare and variably penetrant. Human Molecular Genetics, 5(7), 985–988. https://doi.org/10.1093/hmg/5.7.985