A Presenilin-1 Truncating Mutation Is Present in Two Cases with Autopsy-Confirmed Early-Onset Alzheimer Disease Carolyn Tysoe, Joanne Whittaker, John.

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A Presenilin-1 Truncating Mutation Is Present in Two Cases with Autopsy-Confirmed Early-Onset Alzheimer Disease Carolyn Tysoe, Joanne Whittaker, John Xuereb, Nigel J. Cairns, Marc Cruts, Christine Van Broeckhoven, Gordon Wilcock, David C. Rubinsztein The American Journal of Human Genetics Volume 62, Issue 1, Pages 70-76 (January 1998) DOI: 10.1086/301672 Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 1 Age at onset for EOAD cases studied. Age at death is shown for individuals whose age at onset was not known. The American Journal of Human Genetics 1998 62, 70-76DOI: (10.1086/301672) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 2 Detection of splice-donor-site mutation, by direct sequence analysis of PS-1 exon 4/ intron 4 junction. A, G, A, T, and C reactions were performed in reverse orientation by use of primer 4-2. We have indicated the complementary sequence (corresponding to the sense strand) on the right side of panel A, with the 5′ end at the top. A heterozygous 1-bp deletion was detected in two individuals (lanes 2 and 7 of each set of reactions), resulting in the loss of a G from the GT splice-donor consensus site of intron 4. Exonic and intronic sequences are represented by uppercase and lowercase letters, respectively. The splice-site mutation destroys a PvuII restriction site (boxed). B, PCR analysis of PS-1 exon 4 and the flanking splice sites, to screen for the presence of the PvuII restriction site. Lanes “WT,” Individual lacking the splice-site mutation. Lanes “MUT,” Individual heterozygous for the splice-site mutation. U = uncut; and C = cut. The American Journal of Human Genetics 1998 62, 70-76DOI: (10.1086/301672) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 3 cDNA analysis of RNA extracted from brain tissue with and without the splice-donor-site mutation. PCR primers located in exons 3 and 5 were used to amplify across exon 4. A cDNA sample without the mutation (lane 1) produced bands of 374 bp and 362 bp (top arrow), corresponding to the full-length (+VRSQ) and short (−VRSQ) transcripts (i.e., exon 3 and the complete exon 4 spliced to exon 5). Two shorter transcripts were detected in cDNA from individuals with the mutation (lanes 2 and 3): intermediate products of 205 bp (+VRSQ) and 193 bp (−VRSQ), containing the first 82 bp of exon 4 (middle arrow), and shorter products of 123 bp (+VRSQ) and 111 bp (−VRSQ), which completely lack exon 4 (bottom arrow). The sizes of these bands were precisely determined by sequence analysis (see fig. 4 and Results). The box at the 3′ end of exon 3 represents the alternatively spliced VRSQ motif. The American Journal of Human Genetics 1998 62, 70-76DOI: (10.1086/301672) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 4 Genomic sequence of PS-1, showing mutant and abnormal splice sites. The coding sequence is in uppercase letters, and the intronic sequence is in lowercase letters. Loss of the g (indicated in boldface) from the 5′ splice donor of intron 4 led to abnormal splicing events, which resulted in the removal of all (within boldface square brackets) or part (within boldface parentheses) of exon 4, using a cryptic splice site within exon 4, at position 82 (double underlined). Alternatively spliced nucleotides at the 3′ end of exon 3 are indicated in italics. The positions of primers 3-3F and 5-3R are underlined. The American Journal of Human Genetics 1998 62, 70-76DOI: (10.1086/301672) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 5 Putative amino acid sequence of wild-type PS-1 and truncated protein products, resulting from the introduction of premature-termination codons. All three transcripts have a common N-terminal region (amino acids 1–30). The full-length PS-1 transcript codes for a protein product of 467 amino acids (amino acids 1–100 are shown; top line). However, two shorter transcripts (shown in fig. 4) code for truncated protein products of 77 (middle line) and 70 (bottom line) amino acids, which diverge from the wild-type sequence at codons 57 and 31, respectively. The American Journal of Human Genetics 1998 62, 70-76DOI: (10.1086/301672) Copyright © 1998 The American Society of Human Genetics Terms and Conditions

Figure 6 Pedigree of individual with a splice mutation and a family history of EOAD. The individual carrying the splice mutation is indicated by the arrow. All affected individuals (except II.8) died of AD in their early 40s. The American Journal of Human Genetics 1998 62, 70-76DOI: (10.1086/301672) Copyright © 1998 The American Society of Human Genetics Terms and Conditions