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Early-onset Alzheimer's disease with a presenilin-1 mutation at the site corresponding to the volga German presenilin-2 mutation.

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Early-Onset Alzheimer’s
Disease with a Presenilin- 1
Mutation at the Site
Corresponding to the Volga
German Presenilin-2
Mutation
Richard Crook, BSc,*t Ronald Ellis, MD,$
Megan Shanks, MD,* Leon J. Thal, MD,$
Jordi Perez-Tur, PhD,*t Matt Baker, BSc,*t
Mike Hutcon, PhD,*t Tuomas Haltia, PhD,§
John Hardy, PhD,*t and Douglas Galasko, MD$
We describe a new mutation causing Alzheimer’s disease
(AD)in presenilin-1 (N135D)that is at the homologous
site to the presenilin 2 mutation (N’*’I) in Volga German kindreds. The phenotype of PS1 N’35Dis an earlyonset (34-38 years) disease. The mutation forms part of,
and extends, the a-helical array of mutations in transmembrane 2 of the presenilins and leads to the suggestion that disruption of this helical face is the molecular
insult that leads to disease.
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;42:124-128
Alzheimer’s disease (AD) is the major cause of dementia in the elderly, but also occurs, both sporadically and
in an autosomal dominant form in younger persons
(30-60 years). Three genetic loci have been implicated
in the early-onset form of the disease, ie, the amyloid-P
precursor protein (APP) gene [ I ] on chromosome 21,
the presenilin-1 gene ( P S l ) gene [2] on chromosome
14, and the presenilin-2 (PS2) gene [3, 41 on chromosome 1. Mutations in the PSl gene appear to constitute about 50% of the cases of this form of the dis-
From the *Suncoast Alzheimer’s Disease Laboratories, Departments
of Psychiatry, Pharmacology, Neurology, and Biochemistry, University of South Florida, Tampa, and tBirdsall Building, Mayo Clinic
Jacksonville, Jacksonville, FL; $Department of Neurosciences, University of California, San Diego, and San Diego Veterans Administration Medical Center, San Diego, CA; and %Institutefor Biomedical Sciences, Department of Medical Chemistry, University of
Helsinki, Helsinki, Finland.
Received Oct 22, 1996, and in revised form Dec 26. Accepted for
publication Dec 30, 1996.
Address correspondence to Dr Hardy, Birdsall Building, Mayo
Clinic Jacksonville, 4500 Sari Pablo Rd, Jacksonville, FL 32224.
124
Copyright 0 1997 by the American Neurological Association
ease [2,5-71 with mutations in the APP and PS2 genes
making up about 10% each [5] (although these figures
are only approximations and await the gathering of
genuinely epidemiological data).
PSI I2 encode two similar proteins that are generally
predicted to have 7 transmembrane domains. The
functions of these proteins are not known, but they are
similar to two Caenorhabditis elegans proteins, Spe-4
[8] and Sel-12 [9], that are involved in spermatogenesis
and cell fate determination through the lin-l2/Notch
signaling pathway, respectively. Our colleagues have recently shown that AP42(43) is increased in the plasma
of individuals with PSI12 mutations and in medium
conditioned by skin fibroblasts from such individuals
[ 101, and we have shown that transgenic mice expressing mutant PS1 produce more AP42(43) [ l l ] ,but the
precise connection between PSI I2 and pAPP processing remains obscure.
All but one of the mutations reported in the PSI
gene have been missense changes 12, 4-61, the single
exception being a splice-site acceptor mutation that results in the deletion of exon 9 [ 5 ] in frame [12].Although there are mutations at scattered sites throughout PSI with the exception of the extreme N- and
C-terminal domains and the central part of the loop
between exons 6 and 7 , there is also clear evidence for
clustering, with two defined clusters, the first in transmembrane domain 2, where a series of mutations line
up on one side of an a-helix 151, and the second in
exon 8, where 30% of the mutations occur at the beginning of the large loop between putative transmembrane domains 6 and 7 [13, 141. This latter cluster is
close to a position at which PSI is cleaved and it is
possible that alteration of this cleavage underlies the
pathogenicity of these mutations [ 151. Another interesting feature of the PSI mutations is that all so far
reported alter residues that are conserved in PS2. In a
similar manner, the two pathogenic mutations reported
in PS2 (N1*’I in the Volga German kindreds [3] and
M2”V in an Italian kindred 13, 41) alter residues that
are conserved in PSI; however, a pronounced difference in the phenotype of PS1 encoded disease and
those cases of PS2 encoded disease described so far is
that PSI encoded disease shows a generally early and
constant onset age, whereas the PS2 mutations appear
t o lead to a much more variable onset age [3, 41. It is
not clear whether this is a mutation-specific effect or
relates t o slightly different roles for the presenilins in
the pathogenesis of disease.
With this background, and as a clinical responsibility, we have sought to identify more families with
presenilin-encoded disease and to identify pathogenic
mutations.
Patients and Methods
Ascertainment and Clinical Details
The proband comes from a Mexican-American family with a
history of early-onset dementia spanning at least 4 generations. She had a history of developmental delay and required
special schooling to complete a 10th grade education. She
was initially evaluated and followed at a psychiatric clinic for
symptoms of apathy and depression that began in her early
30s, and she received treatment with antidepressants for several years. Despite this treatment, her symptoms did not improve. Because several members of her family had a history
of dementia accompanied by abnormal movemencs, a test for
Huntington’s disease gene was performed, which revealed a
normal number of triplet repeats.
Neurological evaluation was sought, at age 38, in 1995,
when the patient showed evidence of progressive cognitive
decline. According to informants, the cognitive changes were
evident at age 35. Initially, she had difficulty remembering
the details of conversations and preparing meals, followed by
slowing and impairment of language output, and deterioration of her ability to perform household chores. Myoclonic
jerking of her arms began early in 1996, and by the end of
the year she needed help with dressing and was unable to
write coherently.
O n mental status testing, she was oriented for name only.
Her responses were slow and monotonous. She could repeat
a sentence or a brief word list, but recalled 0 of 3 items after
a delay. She also showed impairment of confrontation naming, writing and copying drawings, calculation, and category
fluency. She scored 77 of 144 on the Mattis Dementia Rating Scale [16], with deficits on every subscale of that test.
Neurological examination was noteworthy for difficulty with
performing movements on command with her left arm and
hand, suggesting apraxia, myoclonic twitching of both arms,
and a slow and somewhat broad-based gait. In addition, the
examination suggested apraxia of her left leg.
Laboratory workup included a panel of dementia blood
rests (all normal), cerebrospinal fluid examination (normal),
a magnetic resonance image of the brain (normal), and an
electroencephalogram that showed slight diffuse slowing. Because of the diagnostic uncertainty and the history of a familial neurodegenerative disorder, a brain biopsy was performed during that hospitalization. Examination of the
frontal lobe tissue sample showed mild loss of neurons and
secondary gliosis. Sections of the frontal lobe biopsy showed
neocortex with a mild loss of neurons and secondary gliosis.
The neuropil was studded with multiple neuritic plaques visible even with hemotoxylin and eosin staining. There were
also abundant neocortical neurofibrillary tangles, to an extent
that nearly every neuron contained a tangle. Microglia were
increased diffusely and in association with neuritic plaques.
There was no inflammation and no evidence of neoplasia.
On sections with the Bielschowsky stain, more than 30 neuritic plaques and dozens of neurofibrillary tangles could be
counted per 1OX field.
O f 7 other siblings, a brother and sister were examined.
The brother had a history of gradual cognitive decline over
the past 5 years, beginning at the age of 36, leading to inability to perform his job and early retirement at age 40. He
did not have psychiatric symptoms or significant medical his-
Brief Communication: Crook et al: Presenilin-1 Alzheimer’s Disease
125
tory. He scored 21 of 30 on the Mini-Mental State Examination [17], and on psychometric testing showed deficits on
tests of orientation, memory (particularly delayed recall),
naming, abstraction, and calculation. His neurological examination was normal. He met clinical criteria for probable
AD. The sister (aged 40) had no significant cognitive symptoms and performed normally on tests of memory and other
abilities.
Five remaining siblings, age 32 to 37 years, were not evaluated but apparently do not have symptoms of memory impairment. Details of the remainder of the pedigree, ascertained through interviewing several family members and
examining limited medical records on the proband’s mother,
are shown. Although autopsy confirmation was not obtained,
the clinical history is strongly suggestive of primary progressive dementia in those individuals indicated (Fig 1) and follows a pattern consistent with autosomal dominant inheritance.
DNA Preparation and Genetic Analysis
Genomic DNA was prepared from buffy coat preparations of
blood samples from 3 siblings discussed above, 2 with AD
and 1 clinically normal. DNA sequencing of the PS1 gene
was performed as we have previously described [6].
Results and Discussion
Sequencing of exon 5 [5] of the PSI gene revealed an
A-to-G transition, altering the predicted sequence at
codon 135 from asparagine to aspartic acid (N’35D).
The sequences of all other exons were normal. This
N’35D mutation was found in 2 affected individuals
(see Fig 1) but not in their unaffected sibling. It is, in
all likelihood, pathogenic. This new mutation is of particular interest for two reasons. First, it alters the residue corresponding to the Volga German mutation in
PS2 (N14’I), and second, it clearly forms part of and
extends the cluster of mutations in the second transmembrane domain (TM2) of PS1 (Fig 2).
The age of onset in this family, unlike that of the
Fig 2. A three-dimensional model of the second transmembrane (TM2) domain of presenilin-1. The mutation reported
here (N135D) at the N-terminus o f helix has been introduced
to the model and is shown in yellow. The other residues in
which mutations have been found earlier are colored red. The
four residues constitute a continuous suface that probably mediates an interaction with another transmembrane helix.
Mokculur Modeling
Transmembrane segments were identified by using the prediction method of Rost and co-workers [18, 191. The sequences of PSI, PS2, mouse PSI, sel-12, and spe-4 [2, 3, 8 ,
91 were used as the input for the program, which generates a
multiple sequence alignment and makes use of its information content in the prediction. Transmembrane segment 2 of
PS1 (residues
to L ~ s ’ was
~ ~ )modeled as a righthanded a-helix using the Biopolymer module of Insight 11,
version 95.0 (BIOSYM), on a Silicon Graphics Indigo 2
workstation.
Fig 1. The pedigree.
6 WW+@
Onset=37yOnset=34y
45y
41Y
Onset=36y
4oY
Oni:Y36y
3 7 ~
126 Annals of Neurology
35y
Vol 42
34y
33y
68y
32y
N o 1 July 1997
Volga German kindreds, appears relatively constant.
This observation suggests, although does not prove,
that the age of onset differences are likely to be dependent on the molecule, rather than the mutation;
namely, there is something about the role of PS2 in
AD that leads to mutations in the molecule having
more variable onset ages.
The Table shows the mutations in this segment of
the protein. The pathogenic mutations occur at an interval of three or four residues, which, assuming
a-helical secondary structure for TM2, suggests that
the residues fall on the same side of the TM2 helix [6].
This TM2 sequence is highly conserved among human, mouse, and one of the C. elegans proteins (Sel12) (>50% identical residues), whereas in the other C.
elegans homologue, Spe-4, only two strictly invariant
residues are found, although one of these is the residue
equivalent to N135 in PSl. The cluster of mutations
in TM2 modeled as a classic right-handed a-helix with
3.6 residues per turn is shown in Figure 2. N'35D is
shown in yellow, whereas the other three residues in
which mutations have been found are shown in red
(see, also, the Table). The lining up of these mutations
on one face of the helix is apparent, validating the notion that this part of the molecule is likely to be
a-helical. Furthermore, that the mutated residues comprise one side of the TM2 helix suggests that there is a
critical function of this face that these mutations disturb. Such a function could be participation of the face
in the formation of a transmembrane channel of some
description, as suggested previously [6]. Alternatively,
the helical face could interact with another transmembrane domain. The latter hypothesis is supported by
two facts. (1) Apart from N135 (see below), all the
mutated residues are hydrophobic, favoring a structural
rather than functional role for these residues [2O]. (2)
Most of the pathogenic mutations involve a substitution with a hydrophobic residue of different size and/or
a change from nonbranched to a branched side chain
(see the Table). In a model system in which the sequence requirements for dimerization of two identical
transmembrane helices have been studied, even rather
conservative single mutations (such as valine to leucine
or vice versa) can lead to disruption of the dimers
([21], reviewed in Reference 20). So it is conceivable
that the pathogenic mutations in TM2 of PS1 disrupt
an interaction, crucially dependent on amino acid sequence, between TM2 and another transmembrane helix.
As discussed above, N'35 is invariant in all presenilin
homologues known to date. The reason for this might
be that the residue occupies a special position, namely,
the so-called N-cap position at the N-terminus of
TM2 [22]. The N-cap residue has an important role as
a helix initiator. In single-span type I membrane proteins that have an extracellular N-terminus, asparagines
are enriched in the N-terminal flank of the transmembrane domain [23], and in multispanning membrane
proteins asparagines are predominantly found in the
extracellular flank of transmembrane domains [24].
Moreover, a mutation data matrix [25] shows that asparagines tend to be highly conserved in multispanning
membrane proteins (whereas the opposite is true for
soluble proteins and proteins with a single transmembrane span). One of the factors behind this trend is
probably the need for accurate positioning of the transmembrane helices; subtle side-to-side interactions between transmembrane helices are critical for maintaining the folded structure of membrane proteins, and
Table. Analysis of the Pathogenic Mutations in the Second Transmembrane Domain of Presenilin-1"
Mutation
Type of Change in Residue
Polarity
Change in Residue
Size
Type of Change in Side Chain
Structure
N'35D
Polar -+ charged
Decreases
Polar + hydrophobic
Increases
Remains hydrophobic
Remains hydrophobic
Hydrophobic -+ mildly polar
Hydrophobic -+ mildly polar
Does not change
Decreases
Decreases
Decreases
Remains hydrophobic
Increases
Remains hydrophobic
Remains hydrophobic
Does not change
Decreases
Hydrogen-bonding capability
change
?-Branched + @-branched;
hydrogen-bonding capability
lost
Straight-chain -+ P-branched
Straight-chain -+ P-branched
Straight-chain + P-branched
Hydrogen-bonding capability
change
P-Branched -+ y-branched
(aromatic)
Straight-chain + y-branched
Straight-chain -+ P-branched
"See Reference 13 for review.
Brief Communication: Crook et al: Presenilin-1 Alzheimer's Disease
127
this in turn requires that the helices begin in exactly
determined positions. Thus, the N’”D mutation
could interfere with helix initiation and lead to a mispositioning of the helical interaction surface.
In conclusion, we have described a new mutation in
the presenilin-1 gene, N’35D,which leads to dementia
with a fairly constant onset age of about 36 to 40
years. The mutation is a new member of the transmembrane domain 2, a-helical array of mutations.
This study was supported by the NIHlNIA program project grant
(M.H., J.H.), by an American Health Assistance Foundation grant,
and by AGO5131 (D.G., L.T.), the Academy of Finland (T.H.),
and the Magnus Ehmrooth Foundation (T.H.).
The family members are thanked for enthusiasm and support.
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