A Pedigree With a Novel Presenilin 1 Mutation at a Residue That Is Not Conserved in Presenilin 2

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Abstract
THE MAJORITY of known pedigrees of early-onset familial Alzheimer disease (AD) are linked to mutations in the presenilin 1 (PS1) gene on chromosome 14.1 At present, 47 missense mutations at 36 different codons and a point mutation upstream of a splice acceptor site that results in an in-frame deletion have been described in the PS1 gene in patients with early-onset AD.2,3 A further autosomal dominant locus for familial AD in Volga German kindreds was demonstrated on chromosome 1,4,5 and the responsible gene is now called the presenilin 2 (PS2) gene. PS1 and PS2 share overall amino acid sequence identity of 63%.4,5 The presenilins also share substantial sequence homologies with the Caenorhabditis elegansSEL-12.6 In addition, a recent study showed that both PS1 and PS2 can functionally replace C elegans SEL-12, confirming that SEL-12 is a bona fide presenilin.7 Protein topology studies of PS1 and SEL-12 confirmed that presenilins are integral membrane proteins with 6 to 8 transmembrane domains.8,9 Most PS1 mutations documented so far occur at residues that are conserved in the presenilin family. All presently known mutations of PS1 and PS2 are in nucleotides coding for amino acids that are conserved between the 2 presenilins, suggesting a functional significance of these residues.