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American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1998 Jan;62(1):70–76. doi: 10.1086/301672

A presenilin-1 truncating mutation is present in two cases with autopsy-confirmed early-onset Alzheimer disease.

C Tysoe 1, J Whittaker 1, J Xuereb 1, N J Cairns 1, M Cruts 1, C Van Broeckhoven 1, G Wilcock 1, D C Rubinsztein 1
PMCID: PMC1376799  PMID: 9443865

Abstract

We have examined genomic DNA from 40 cases of autopsy-confirmed early-onset Alzheimer disease (EOAD) (age at onset <=65 years) that were all unselected for family history. We have sequenced the 10 exons and flanking intronic sequences of the presenilin-1 (PS-1) gene for all 40 individuals. A single mutation, a deletion of a G from the intron 4 splice-donor consensus sequence, was detected in two individuals in this study. The mutation was associated with two shortened transcripts, both with shifted reading frames resulting in premature-termination codons. All the PS-1 mutations described elsewhere have been missense or in-frame splice mutations, and recent data suggest that these result in disease by gain-of-function or dominant-negative mechanisms. The mutation that we have identified is likely to result in haploinsufficiency and would be most consistent with other mutations acting in a dominant-negative manner. However, we cannot exclude the possibility that the small amounts of truncated transcripts exert a gain of function. Since no other mutations or polymorphisms were detected in our patients, mutations in the coding regions and splice consensus sequences of PS-1 are likely to be rare in EOAD cases unselected for family history.

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Selected References

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