Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr21:27269939 G>T, Chr21:27269938 A>C
dbSNP ID: rs63751263, rs63750445
Coding/Non-Coding: Coding
Mutation Type: Point, Double
Codon Change: AAG.ATG to AAT.CTG
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 16
Research Models: 74

Findings

The only known mutation immediately adjacent to the β-secretase site in APP, the Swedish mutation is actually a double mutation, resulting in a substitution of two amino acids, lysine (K) and methionine (M) to asparagine (N) and leucine (L). This well-known mutation has been reported in two large Swedish families who were found to be connected genealogically. Affected individuals generally presented first with memory loss and all met diagnostic criteria for Alzheimer's disease (Mullan et al., 1992).

The two substitutions underlying this mutation are absent from the gnomAD variant database (gnomAD v.2.1.1, Oct 2021).

Neuropathology

Generalized atrophy with sulcal widening and mild ventricular enlargement was observed in one autopsied case (Mullan et al., 1992).

Biological Effect

In vitro, this mutation repeatedly has been shown to increase total Aβ levels. Specifically, there is increased production and secretion of Aβ40 and Aβ42 (Scheuner et al., 1996; Nilsberth et al., 2001; Ancolio et al., 1999; Johnston et al., 1994; Citron et al., 1994; Citron et al., 1992; Cai et al., 1993). The ratio of Aβ40/Aβ42 is generally not affected.

The PHRED-scaled CADD score, which integrates diverse information in silico, was above 20 for each of the substitutions, suggesting that, at least individually, they have deleterious effects (CADD v.1.6, Oct 2021).

Research Models

The Swedish mutation is commonly introduced into mouse models of AD because it strongly enhances overall Aβ production. Mice carrying this mutation, such as the Tg2576, J20, and 3xTg models, among many others, tend to accumulate high levels of Aβ and develop amyloid pathology.

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References

Research Models Citations

1. Tg2576
2. J20 (PDGF-APPSw,Ind)
3. 3xTg

Paper Citations

1. Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B, Lannfelt L. A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet. 1992 Aug;1(5):345-7. PubMed.
2. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, Larson E, Levy-Lahad E, Viitanen M, Peskind E, Poorkaj P, Schellenberg G, Tanzi R, Wasco W, Lannfelt L, Selkoe D, Younkin S. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med. 1996 Aug;2(8):864-70. PubMed.
3. Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow DB, Younkin SG, Näslund J, Lannfelt L. The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci. 2001 Sep;4(9):887-93. PubMed.
4. Ancolio K, Dumanchin C, Barelli H, Warter JM, Brice A, Campion D, Frébourg T, Checler F. Unusual phenotypic alteration of beta amyloid precursor protein (betaAPP) maturation by a new Val-715 --> Met betaAPP-770 mutation responsible for probable early-onset Alzheimer's disease. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):4119-24. PubMed.
5. Johnston JA, Cowburn RF, Norgren S, Wiehager B, Venizelos N, Winblad B, Vigo-Pelfrey C, Schenk D, Lannfelt L, O'Neill C. Increased beta-amyloid release and levels of amyloid precursor protein (APP) in fibroblast cell lines from family members with the Swedish Alzheimer's disease APP670/671 mutation. FEBS Lett. 1994 Nov 14;354(3):274-8. PubMed.
6. Citron M, Vigo-Pelfrey C, Teplow DB, Miller C, Schenk D, Johnston J, Winblad B, Venizelos N, Lannfelt L, Selkoe DJ. Excessive production of amyloid beta-protein by peripheral cells of symptomatic and presymptomatic patients carrying the Swedish familial Alzheimer disease mutation. Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):11993-7. PubMed.
7. Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Lieberburg I, Selkoe DJ. Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production. Nature. 1992 Dec 17;360(6405):672-4. PubMed.
8. Cai XD, Golde TE, Younkin SG. Release of excess amyloid beta protein from a mutant amyloid beta protein precursor. Science. 1993 Jan 22;259(5094):514-6. PubMed.

Further Reading