by John Hardy, National Institute on Aging, Bethesda, MD
Diagram by Richard Crook, Mayo Clinic Jacksonville
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
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 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.,
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 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)
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
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