Several families with an early-onset form of familial Alzheimer's disease have been found to harbour mutations at a specific codon (717) of the gene for the beta-amyloid precursor protein (APP) on chromosome 21. We now report, a novel base mutation in the same exon of the APP gene which co-segregates in one family with presenile dementia and cerebral haemorrhage due to cerebral amyloid angiopathy. The mutation results in the substitution of alanine into glycine at codon 692. These results suggest that the clinically distinct entities, presenile dementia and cerebral amyloid angiopathy, can be caused by the same mutation in the APP gene.

Helix numbering system Helices are given a different number if separated by a multibranched loop (e.g. helices 9 and 10), by a pseudoknot loop (e.g. helices 1 and 2), or by a single stranded area that does not * To whom correspondence should be addressed k.

Helix numbering system Helices are given a different number if separated by a multibranched loop (e.g. helices 9 and 10), by a pseudoknot loop (e.g. helices 1 and 2), or by a single stranded area that does not * To whom correspondence should be addressed k.

No abstract

A positional cloning approach has led to the identification of two closely related genes, the presenilins (PS), for autosomal dominant presenile Alzheimer disease (AD): PS-1 at 14q24.3 and PS-2 at 1q31-q42. The PS-1 gene was identified by direct cDNA selection of yeast artificial chromosomes containing the candidate chromosomal region. Subsequently, the PS-2 gene was identified due to its high sequence homology with PS-1 and its location within the candidate region defined by linkage studies. To date, 30 different missense mutations and one in-frame splice site mutation were described in PS-1, while only two missense mutations were detected in PS-2, suggesting that PS-1 mutations are more frequently involved in familial presenile AD. The PS transcripts encode novel proteins that resemble integral transmembrane proteins of roughly 450 amino acids and at least seven transmembrane domains. The genomic organization of the PS genes is very similar showing that full length PS-1 and PS-2 are encoded by 10 exons. However, different alternative splicing patterns have been observed for PS-1 and PS-2 indicating that the corresponding proteins (ps-1 and ps-2) may have similar but not identical biological functions.