View Presenilin-1 Diagram (2006 version by K. Dillen and W. Annaert)
View Presenilin-1 Diagram (2002 version by R. Crook)
View Presenilin-1 Mutations Table

View Presenilin-2 Diagram
View Presenilin-2 Mutations Table

With the realization that the APP gene accounted for only a minority of cases of autosomal dominant Alzheimer's disease (see APP Mutation Directory), the race was on to find other gene(s) that might lead to this form of the disease. This was perceived as an important goal in its own right, but it was also felt that it might offer some independent test of the 'amyloid cascade hypothesis.' With the benefit of hindsight, there had been some evidence that chromosome 14 might be involved, as there was an-all-but-forgotten linkage report suggesting a locus towards the telomere of chromosome 14 (Weitkamp et al., 1983). The first proper report of genetic linkage, however, came from the Seattle group (Schellenberg et al., 1992) and was quickly followed by confirmatory reports from other major groups (St. George-Hyslop et al., 1992, Van Broeckhoven et al., 1992, Mullan et al., 1992). Clearly, the major locus for early onset, autosomal dominant Alzheimer's disease was on chromosome 14q. Significantly, the Volga German group of families did not show linkage to this locus, strongly suggesting that there was also a third locus.

Gradually, the region containing the locus was narrowed down (Cruts et al., 1995), and efforts intensified to try and clone the gene using classical positional cloning strategies (because none of the candidate genes known to be in the region had mutations). In a tour de force, Sherrington and colleagues identified presenilin 1 (1995). Unlike the case of APP, there were no previous data implicating the presenilins in Alzheimer's disease, and Sherrington and colleagues only knew it was the gene for one reason—the best possible: all their "linked" families had mutations. In the meantime, the Seattle group had identified a linkage to chromosome 1 in the Volga German families, but this finding was 'in press' when the cloning of presenilin 1 was published (Levy-Lahad et al., 1995a). As soon as each group learned of the structure of the presenilin 1 protein, they searched databases for homologies and realized that a very similar gene was located on chromosome 1. Sure enough, this second gene mapped into the Volga German region and mutations were quickly identified in this gene, presenilin 2 (Levy-Lahad et al., 1995b, Rogaev et al., 1995).

The two genes are highly homologous at the DNA sequence, protein sequence, and gene structure levels (Alzheimer's Collaborative Group, 1995). The proteins are believed to have either 6 or 8 transmembrane domains. A large number of mutations have now been found (see table, diagram, and http://molgen-www.uia.ac.be/ADMutations/). The function of the presenilins and their mode of dysfunction in Alzheimer's disease are largely outside the scope of this review. However, with regard to their function, a key observation has been that they are homologous to the C. elegans proteins sel-12 and spe-4 (Levitan and Greenwald, 1995, L'Hernault and Arduengo, 1992) and are involved in the Notch signalling pathway (Levitan et al., 1996, Baumeister et al., 1997). With regard to their dysfunction in Alzheimer's disease, the observation that they lead to altered APP processing in the same apparent way as APP717 mutations, in patients with mutations has proved to be of seminal importance (Scheuner et al., 1996) and replicable in both transfected cells (Citron et al., 1997, Mehta et al., 1997) and transgenic animals (Borchelt et al., 1996, Duff et al., 1996).

Most of the pathogenic mutations are missense mutations to residues which are conserved between the two proteins. They are not randomly distributed, but cluster in exon 8 and along faces of the transmembrane alpha-helices (Crook et al., 1997, Perez-Tur et al., 1996). There are, however, a few exceptions to rule this rule, as described below:

The Delta 9 mutation

The delta 9 mutation can be caused by mutations in the splice acceptor site of exon 9 (Perez-Tur et al., 1995: Sato et al., 1998) or by deletion of the whole genomic section of the gene (Prihar et al., 1999). The mutation results in the deletion of residues 291-319 of the protein and the change of S290C at the splice site. The deletion alters the metabolism of presenilin as it deletes the major cleavage site of presenilin 1 (Thinakaran et al., 1996: Podlisny et al., 1997). Despite this major effect on presenilin metabolism, recent data has suggested that the "pathogenic" mutation is S290C since simply changing this residue affects APP metabolism in the same way as the full mutation (Steiner at al., 1999).

The delta 9 mutation is the one most associated with an unusual pathological and clinical phenotype (Crook et al., 1998). In this phenotype, spastic paraparesis is the first symptom, followed several years later by a dementing process. The pathology of individuals with this mutation are not the conventional neuritic plaques of Alzheimer's disease, but rather large "cotton wool" plaques without neuritic reaction or a evidence of glial reactivity. Other mutations also sometimes lead to this phenotype (Kwok et al., 1997). The relation of the delta 9, and other presenilin mutations to the unusual pathology and the relation of both the mutation and the pathology to the clinical features remains unclear: it may be of significance that the delta 9 mutation has a particularly large effect on APP processing (Mehta et al., 1998, Citron et al., 1997).

The Delta 4 mutation

The delta 4 mutation is a splice donor site mutation (Tysoe et al. 1998). This mutation causes a large number of different transcripts many of which are truncated: however the pathogenic transcript is almost certainly the one with a simple insertion in at the splice site (T113-114ins). This transcript, like all the other missense mutations tested, increases A-beta-42 production in transfected cells (DeJonghe et al., 1999). This mutation illustrates well the fact that all the pathogenic mutations maintain the overall structure of the protein and all mutations affect APP processing (Murayama et al., 1999)

Are there any other pathogenic loci for early onset autosomal dominant Alzheimer's disease?

Epidemiological studies suggest that the APP and presenilin mutations together account for a fairly small proportion of cases of early onset disease, even amongst those designated as 'familial' (Cruts et al., 1998). However, we are not aware of the existence of any families that lack any of these known mutations and have multiply affected individuals over three generations with cousins affected by the same disease. This suggests, but does not prove, that the simple pathogenic loci have all been identified, and that other familial clustering is likely to be oligogenic rather than monogenic in etiology.

View Presenilin-1 Diagram (2006 version by K. Dillen and W. Annaert)
View Presenilin-1 Diagram (2002 version by R. Crook)
View Presenilin-1 Mutations Table

References

Alzheimer's Disease Collaborative Group. The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families. Nat Genet 1995 Oct;11(2):219-22. Abstract.

Baumeister R, Leimer U, Zweckbronner I, Jakubek C, Grunberg J, Haass C Human presenilin-1, but not familial Alzheimer's disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing. Genes Funct 1997 Apr;1(2):149-59. Abstract.

Borchelt DR, Ratovitski T, van Lare J, Lee MK, Gonzales V, Jenkins NA, Copeland NG, Price DL, Sisodia SS Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 1997 Oct;19(4):939-45. Abstract.

Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe DJ Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med 1997 Jan;3(1):67-72. Abstract.

Crook R, Verkkoniemi A, Perez-Tur J, Mehta N, Baker M, Houlden H, Farrer M, Hutton M, Lincoln S, Hardy J, Gwinn K, Somer M, Paetau A, Kalimo H, Ylikoski R, Poyhonen M, Kucera S, Haltia M A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med 1998 Apr;4(4):452-5. Abstract.

Crook R, Ellis R, Shanks M, Thal LJ, Perez-Tur J, Baker M, Hutton M, Haltia T, Hardy J, Galasko D Early-onset Alzheimer's disease with a presenilin-1 mutation at the site corresponding to the Volga German presenilin-2 mutation. Ann Neurol 1997 Jul;42(1):124-8. Abstract.

Cruts M, Backhovens H, Theuns J, Clark RF, Le Paslier D, Weissenbach J, Goate AM, Martin JJ, Van Broeckhoven C Genetic and physical characterization of the early-onset Alzheimer's disease AD3 locus on chromosome 14q24.3. Hum Mol Genet 1995 Aug;4(8):1355-64. Abstract.

Cruts M, van Duijn CM, Backhovens H, Van den Broeck M, Wehnert A, Serneels S, Sherrington R, Hutton M, Hardy J, St George-Hyslop PH, Hofman A, Van Broeckhoven C Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet 1998 Jan;7(1):43-51. Abstract.

De Jonghe C, Cruts M, Rogaeva EA, Tysoe C, Singleton A, Vanderstichele H, Meschino W, Dermaut B, Vanderhoeven I, Backhovens H, Vanmechelen E, Morris CM, Hardy J, Rubinsztein DC, St George-Hyslop PH, Van Broeckhoven C Aberrant splicing in the presenilin-1 intron 4 mutation causes presenile Alzheimer's disease by increased Abeta42 secretion. Hum Mol Genet 1999 Aug;8(8):1529-40. Abstract.

Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton M, Buee L, Harigaya Y, Yager D, Morgan D, Gordon MN, Holcomb L, Refolo L, Zenk B, Hardy J, Younkin S Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature 1996 Oct 24;383(6602):710-3. Abstract.

Kwok JB, Taddei K, Hallupp M, Fisher C, Brooks WS, Broe GA, Hardy J, Fulham MJ, Nicholson GA, Stell R, St George Hyslop PH, Fraser PE, Kakulas B, Clarnette R, Relkin N, Gandy SE, Schofield PR, Martins RN. Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype. Neuroreport 1997 Apr 14;8(6):1537-42. Abstract.

Levitan D, Doyle TG, Brousseau D, Lee MK, Thinakaran G, Slunt HH, Sisodia SS, Greenwald I. Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc Natl Acad Sci U S A 1996 Dec 10;93(25):14940-4. Abstract.

Levitan D, Greenwald I. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene. Nature 1995 Sep 28;377(6547):351-4. Abstract.

Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K, et al Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 1995b Aug 18;269(5226):973-7. Abstract.

Levy-Lahad E, Wijsman EM, Nemens E, Anderson L, Goddard KA, Weber JL, Bird TD, Schellenberg GD A familial Alzheimer's disease locus on chromosome 1. Science 1995a Aug 18;269(5226):970-3. Abstract.

L'Hernault SW, Arduengo PM Mutation of a putative sperm membrane protein in Caenorhabditis elegans prevents sperm differentiation but not its associated meiotic divisions. J Cell Biol 1992 Oct;119(1):55-68. Abstract.

Mehta ND, Refolo LM, Eckman C, Sanders S, Yager D, Perez-Tur J, Younkin S, Duff K, Hardy J, Hutton M Increased Abeta42(43) from cell lines expressing presenilin 1 mutations. Ann Neurol 1998 Feb;43(2):256-8. Abstract.

Mullan M, Houlden H, Windelspecht M, Fidani L, Lombardi C, Diaz P, Rossor M, Crook R, Hardy J, Duff K, et al A locus for familial early-onset Alzheimer's disease on the long arm of chromosome 14, proximal to the alpha 1-antichymotrypsin gene. Nat Genet 1992 Dec;2(4):340-2. Abstract.

Murayama O, Tomita T, Nihonmatsu N, Murayama M, Sun X, Honda T, Iwatsubo T, Takashima A Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer's disease. Neurosci Lett 1999 Apr 9;265(1):61-3. Abstract.

Perez-Tur J, Froelich S, Prihar G, Crook R, Baker M, Duff K, Wragg M, Busfield F, Lendon C, Clark RF, et al A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene. Neuroreport 1995 Dec 29;7(1):297-301. Abstract.

Perez-Tur J, Croxton R, Wright K, Phillips H, Zehr C, Crook R, Hutton M, Hardy J, Karran E, Roberts GW, Lancaster S, Haltia T A further presenilin 1 mutation in the exon 8 cluster in familial Alzheimer's disease. Neurodegeneration 1996 Sep;5(3):207-12. Abstract.

Podlisny MB, Citron M, Amarante P, Sherrington R, Xia W, Zhang J, Diehl T, Levesque G, Fraser P, Haass C, Koo EH, Seubert P, St George-Hyslop P, Teplow DB, Selkoe DJ Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 and Ala299 and occur as stable N- and C-terminal fragments in normal and Alzheimer brain tissue. Neurobiol Dis 1997;3(4):325-37. Abstract.

Prihar G, Verkkoniem A, Perez-Tur J, Crook R, Lincoln S, Houlden H, Somer M, Paetau A, Kalimo H, Grover A, Myllykangas L, Hutton M, Hardy J, Haltia M Alzheimer disease PS-1 exon 9 deletion defined. Nat Med 1999 Oct;5(10):1090. Abstract.

Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, et al Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature 1995 Aug 31;376(6543):775-8. Abstract.

Sato S, Kamino K, Miki T, Doi A, Ii K, St George-Hyslop PH, Ogihara T, Sakaki Y Splicing mutation of presenilin-1 gene for early-onset familial Alzheimer's disease. Hum Mutat 1998;Suppl 1:S91-4. No abstract available.

Schellenberg GD, Bird TD, Wijsman EM, Orr HT, Anderson L, Nemens E, White JA, Bonnycastle L, Weber JL, Alonso ME, et al Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14. Science 1992 Oct 23;258(5082):668-71. Abstract.

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. Abstract.

Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K, et al Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 1995 Jun 29;375(6534):754-60. Abstract.

St George-Hyslop P, Haines J, Rogaev E, Mortilla M, Vaula G, Pericak-Vance M, Foncin JF, Montesi M, Bruni A, Sorbi S, et al Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14. Nat Genet 1992 Dec;2(4):330-4. Abstract.

Steiner H, Romig H, Grim MG, Philipp U, Pesold B, Citron M, Baumeister R, Haass C The biological and pathological function of the presenilin-1 Deltaexon 9 mutation is independent of its defect to undergo proteolytic processing. J Biol Chem 1999 Mar 19;274(12):7615-8. Abstract.

Thinakaran G, Borchelt DR, Lee MK, Slunt HH, Spitzer L, Kim G, Ratovitsky T, Davenport F, Nordstedt C, Seeger M, Hardy J, Levey AI, Gandy SE, Jenkins NA, Copeland NG, Price DL, Sisodia SS Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo. Neuron 1996 Jul;17(1):181-90. Abstract.

Tysoe C, Whittaker J, Xuereb J, Cairns NJ, Cruts M, Van Broeckhoven C, Wilcock G, Rubinsztein DC A presenilin-1 truncating mutation is present in two cases with autopsy-confirmed early-onset Alzheimer disease. Am J Hum Genet 1998 Jan;62(1):70-6. Abstract.

Van Broeckhoven C, Backhovens H, Cruts M, De Winter G, Bruyland M, Cras P, Martin JJ Mapping of a gene predisposing to early-onset Alzheimer's disease to chromosome 14q24.3. Nat Genet 1992 Dec;2(4):335-9. Abstract.

Weitkamp LR, Nee L, Keats B, Polinsky RJ, Guttormsen S Alzheimer disease: evidence for susceptibility loci on chromosomes 6 and 14. Am J Hum Genet 1983 May;35(3):443-53. Abstract.