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Biochemical Society Transactions (2012) Volume 40, part 4
Copy number variations involving the
microtubule-associated protein tau in human
diseases
Anne Rovelet-Lecrux*†1 and Dominique Campion*†
*Inserm, U1079, Rouen, France, and †University of Rouen, Institute for Research and Innovation in Biomedicine, Rouen, France
Abstract
Mutations of the MAPT (microtubule-associated protein tau) gene are associated with FTLD (frontotemporal
lobar degeneration) with tau pathology. These mutations result in a decreased ability of tau to bind MTs
(microtubules), an increased production of tau with four MT-binding repeats or enhanced tau aggregation. In
two FTLD patients, we recently described CNVs (copy number variations) affecting the MAPT gene, consisting
of a partial deletion and a complete duplication of the gene. The partial deletion resulted in a truncated
protein lacking the first MT-binding domain, which had a dramatic decrease in the binding to MTs but acquired
the ability to bind MAP (microtubule-associated protein) 1-B. In this case, tauopathy probably resulted from
both a loss of normal function and a gain of function by which truncated tau would sequester another
MAP. In the other FTLD patient, the complete duplication might result in the overexpression of tau, which
in the mouse model induces axonopathy and tau aggregates reminiscent of FTLD-tau pathology. Interestingly, the same rearrangement was also described in several children with mental retardation, autism
spectrum disorders and dysmorphic features, as well as in a schizophrenic patient. Finally, complete deletions
of the MAPT gene have been associated with mental retardation, hypotonia and facial dysmorphism.
Introduction
CNVs (copy number variations) are unbalanced structural
variations of genomic DNA, such as duplications and
deletions. They have originally been defined as ‘segments
of at least 1 kb in size, for which copy number differences
have been observed in the comparison of two or more
genomes’ [1]. With the development of whole-genome
analysis technologies, and since the publication in 2004 of
the first two papers reporting CNVs in healthy people [2,3],
CNVs have been shown to be largely responsible for human
evolution and genetic diversity between individuals, to a
greater extent than SNPs (single nucleotide polymorphisms)
[4,5]. However, when the deleted or duplicated regions
encompass dosage-sensitive genes, rearrangements can lead
to an abnormal phenotype; CNVs have thus been implicated
as risk factors and causative factors in numerous diseases,
referred to as genomic disorders.
Recurrent CNVs are mediated by NAHR (non-allelic
homologous recombination), a mechanism depending on the
presence of LCRs (low copy repeats) of extensive homology
in the genome. Tracts of LCRs of high homology (>95 %) and
length (>1–5 kb) will enable NAHR by unequal crossingKey words: copy number variation, microtubule, neurodegenerative disorder, schizophrenia, tau.
Abbreviations used: CNV, copy number variation; FTDP-17, frontotemporal dementia with
parkinsonism linked to chromosome 17; FTLD, frontotemporal lobar degeneration; LCR, low
copy repeat; MAPT, microtubule-associated protein tau; MT, microtubule; NAHR, non-allelic
homologous recombination; RT, reverse transcription.
1
To whom correspondence should be addressed (email [email protected]).
C The
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Authors Journal compilation over leading to both deletion and duplication of the genomic
fragment located between the LCRs [6]. LCRs represent
8.6 % of the finished sequence on chromosome 17, on which is
located the MAPT (microtubule-associated protein tau) gene,
and duplications and deletions on chromosome 17 have been
implicated in a number of genomic disorders [7]. In the 1990s,
Lupski et al. [8] reported the first disease-associated CNVs,
involving the PMP22 gene, located in the 17p12 region. They
demonstrated that duplications and deletions of this gene
are responsible for Charcot–Marie–Tooth disease and HNPP
(hereditary neuropathy with liability to pressure palsies)
peripheral neuropathies respectively. These rearrangements
are mediated by LCRs referred to as CMT1A-REPs, flanking
the PMP22 gene [8]. To the same extent, the 17q21.31 region
represents a rearrangement-prone interval, because of its
complex genomic architecture and the presence of multiple
LCRs in the surrounding area. These LCRs, which are
arranged in different orientations and present high sequence
homology, have been shown to be the basis of an inversion
polymorphism that is found at a frequency of 20 % in the
European population [9,10]. This inversion results in high
linkage disequilibrium underlying two extended haplotypes
named H1 and H2, and involves four genes: CRHR1, IMP5,
STH and MAPT.
The MAPT gene encodes the tau protein. Tau is an
abundant protein in both the CNS (central nervous system)
and the PNS (peripheral nervous system). In the brain, it is
found predominantly in nerve cells, and more particularly in
axons. The major known physiological function of tau is to
Biochem. Soc. Trans. (2012) 40, 672–676; doi:10.1042/BST20120045
The Biology and Pathology of Tau and its Role in Tauopathies II
Figure 1 Schematic representation of tau isoforms
aa, amino acids; MBD, MT-binding domain.
stabilize the MT (microtubule) network and to promote MT
assembly. The adult human brain expresses six tau isoforms,
derived from the single MAPT gene, by alternative splicing of
exons 2, 3 and 10. Three isoforms (3R-tau) contain three MTbinding domains and the other three isoforms (4R-tau) have
an additional binding domain encoded by exon 10 of MAPT.
Exons 2 and 3 encode two N-terminal inserts, which are not
involved in the binding of tau to MT (Figure 1). In normal
adult human cerebral cortex, three-repeat and four-repeat
isoforms are expressed at a similar level. In the developing
human brain, only the shortest tau isoform (three repeats and
no N-terminal inserts), which binds 3-fold weaker than 4Rtau to the MT, is expressed [11]. Of note, nested into intron 9
of the MAPT gene is the intronless STH gene, which encodes
a 128-amino-acid protein with tissue expression similar to
tau.
Since 1998, mutations of the MAPT gene have been
shown to be responsible for FTDP-17 (frontotemporal
dementia with parkinsonism linked to chromosome 17), a
neurodegenerative disorder characterized by intraneuronal
tau aggregates. This highlighted the crucial role of tau protein
in the adult brain, but the mechanism by which mutated
tau induces neuronal death is still debated; however, it is
commonly admitted that loss of function of tau is insufficient
in inducing such a phenotype, and that mutated tau in
FTDP-17 acquires a toxic gain of function. This is evident
from animal models with knocked-out endogenous tau and
no particular neurodegenerative phenotype. Besides this, a
considerable number of mouse models have been generated,
but overexpression of wild-type or mutated tau in mice only
recapitulate selected aspects of human disease, with regard
to the multiple molecular pathways that have so far been
implicated in FTDP-17 [12].
In the present report, we review the different types of
rearrangements involving the MAPT gene in the human
genome and their phenotypic consequences, and we show
that they are of particular interest in understanding tau
function and the mechanisms by which tau drives pathologies.
Complete deletions of the MAPT gene: the
17q21.31 microdeletion syndrome
In 2006, two papers jointly described 17q21.31 microdeletions in children with hypotonia, mental retardation and facial
dysmorphism [13,14]. The rearrangement corresponded
exactly to the inverted region, meaning that it included the
MAPT, STH, CRHR1 and IMP5 genes. This microdeletion
most probably resulted from NAHR and was linked to the
presence, in the parent of origin of the deletion, of at least
one H2 allele. Clinically, all patients presented developmental
delay with mild to moderate mental retardation and a
characteristic craniofacial dysmorphism including a long face,
a tubular or pear-shaped nose and a bulbous nasal tip. Most
patients had overfriendly behaviour. Other features including
thin pituitary stalk, epilepsy, heart defects and kidney or
urologic anomalies have also been described, but are variable
among patients [13–17]. More recently, Dubourg et al. [15]
reported 14 patients with 17q21.31 microdeletion syndrome.
Two of them carried smaller deletions than the one initially
reported, which enabled refining the minimal critical region
of this syndrome to the MAPT and STH genes only [15].
This suggests that the largest part of the phenotype associated
with the 17q21.31 microdeletion syndrome results from the
deletion of only two genes.
Complete duplications of the MAPT gene
Microduplications of the 17q21.31 region, which are
reciprocal to the 17q21.31 microdeletion, encompass the
MAPT, STH, CRHR1 and IMP5 genes. To date, only
eight cases have been reported in the literature. In contrast
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Biochemical Society Transactions (2012) Volume 40, part 4
with the microdeletion syndrome, in which the associated
phenotype is quite similar between all patients, the phenotype
associated with the 17q21.31 microduplication is highly
variable. The first patient to be reported, in 2007, was a
girl with a severe psychomotor developmental delay and
dysmorphic craniofacial features [18]. Another patient who
was recently described by Kitsiou-Tzeli et al. [17] had the
same phenotype. In 2009, the four patients described by
Grisart et al. [19] also had behavioural problems and poor
social interaction, but were not dysmorphic. In another
study, Guilmatre et al. [20] found this microduplication
in a patient with schizophrenia, and finally, we reported
this microduplication in a patient diagnosed with FTLD
(frontotemporal lobar degeneration) [21]. The phenotype
associated with the 17q21.31 microduplication thus covers a
broad range of disorders, including neurodevelopmental and
neurodegenerative disorders. One should note that the FTLD
patient only carried the H1 haplotype, whereas other patients
all had H1/H2 haplotypes. The genotype of the patient
with schizophrenia has not been reported. The differences of
haplotypes may thus explain the variability of the phenotype.
However, such phenotypic differences may also underlie the
involvement of modifier genes.
Partial deletions of the MAPT gene
Only two partial deletions involving the MAPT gene have
been reported to date. In 2012, Kitsiou-Tzeli et al. [17]
described a patient initially presenting with autism spectrum
disorder, who carried a deletion of the four last exons and 3 UTR (untranslated region) of the MAPT gene, the STH gene
remaining intact. However, this patient also had an Xq21.31
deletion inherited from his mother, which precludes any
conclusion about the causal involvement of the rearrangement
of the MAPT gene.
The other partial deletion was described by our group in
a patient with FTLD, who had an affected mother [22]. This
deletion removed exons 6–9 of the MAPT gene, as well as the
STH gene. In contrast with the large 17q21.31 microdeletions
and microduplications previously described, sequencing
of the breakpoints showed that this rearrangement was
mediated by Alu sequences. This deletion was predicted
to conserve the open reading frame of the mRNA, and
RT (reverse transcription)–PCR analysis confirmed that
truncated isoforms were transcribed. Moreover, RT–PCR
indicated that the alternative splicing of exon 10 was
conserved in the truncated transcripts. Thus two truncated
tau isoforms were predicted to be produced, lacking the first
MT-binding domain and possessing only two or three MTbinding domains, depending on the exclusion or inclusion
of exon 10. We could then demonstrate, using an MT
extraction assay, that truncated tau isoforms had a drastic
reduction in their ability to bind MTs. We also showed using
immunoprecipitation experiments that, in contrast with wildtype tau isoforms, the truncated tau isoforms acquired the
ability to bind MAP1B, another axonal MAP (MT-associated
protein) which has been shown to have redundant functions
C The
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Authors Journal compilation with tau. These results supported the mechanism of tau
toxicity proposed by Alonso et al. [23] from the Iqbal group,
in which the stability of MTs would be severely hampered by a
mechanism involving both a loss of function and a detrimental
gain of function of the truncated protein, ultimately leading
to the loss of axonal transport and cell death.
Conclusions
Finally, the study of CNVs of the MAPT gene reveals
that tau is involved in a large variety of diseases, covering
a broad spectrum of pathologies. MAPT deletions are
involved in a complex microdeletion syndrome essentially
characterized by mental retardation and dysmorphic features;
MAPT duplications lead to a variable phenotype, ranging
from mental retardation with or without dysmorphism, to
schizophrenia and FTLD. And finally, partial deletions lead
to autism in a patient with disruption of the MAPT gene, or
to FTLD in a patient with intragenic partial deletion, leading
to the production of a truncated protein.
Concerning MAPT deletions, the phenotype is quite
similar between patients, whatever the size of the deletion,
including mental retardation but also dysmorphic features.
The deletion encompasses at least the MAPT and STH
genes, but in most cases also covers the CRHR1 and IMP5
genes. Deletion of the MAPT gene in mouse induces muscle
weakness and reduction of axonal size [24,25]. In cellular
models and more recently in mouse models, it has also
been shown that tau reduction affects axonal elongation and
neuronal migration [26]. This would be consistent with the
phenotypes of hypotonia and mental retardation observed
in most patients. However, as tau is essentially expressed in
neurons, and given the phenotype observed in mouse models,
it seems unlikely that the sole MAPT deletion results in
dysmorphic features. This suggests that part of the phenotype
is due to the involvement of one of the three other genes
located in the 17q21.31 region: CRHR1, IMP5 and STH.
CRHR1 encodes the corticotropin-releasing hormone
receptor 1, which is widely expressed in the brain.
Mouse models lacking CRHR1 present behavioural and
developmental phenotypes, such as reduced anxiety, as
well as disruption of the HPA (hypothalamic–pituitary–
adrenal)-axis [27,28]. Interestingly, some of the patients
carrying 17q21.31 microdeletions, besides more common
features, presented a thin pituitary stalk or even disruption
of the pituitary stalk [16]. CRHR1 is thus another good
candidate for a dosage-sensitive gene underlying the 17q21.31
microdeletion syndrome.
IMP5 is an intramembrane protease expressed in the
brain and testis, initially studied regarding its homology
with presenilin. IMP5 has a dual function in nuclear import
receptors and cytoplasmic chaperones [29], but cannot be
specifically linked to one of the phenotypes underlying the
17q21.31 microdeletion syndrome.
The STH gene is, like MAPT, always included in the
deletions. It is highly expressed in the placenta, muscle,
fetal brain and adult brain. In numerous association studies
The Biology and Pathology of Tau and its Role in Tauopathies II
[30–32], it has been shown to interact with tau, but also
with peroxiredoxin 6 [33], which has antioxidant and
phospholipase activity, and with the Abelson kinase [34].
Interestingly, Abelson is widely expressed but is notably
highly expressed in hyaline cartilage [35], which could give us
a link to the dysmorphic features involving notably the nose
in affected patients.
To conclude, both deletions and duplications of the
MAPT gene are detrimental to humans because of their
association with a wide range of phenotypes, including
neurodevelopmental and neurodegenerative diseases. However, we can only suppose that the phenotypes that are
linked to these rearrangements are due to a decrease or
an increase in tau expression; this would require mRNA
and protein studies. Moreover, the phenotypic differences
observed for the same rearrangement, i.e. MAPT duplication,
raise the issue of the involvement of modifier genes. This
underscores the challenges that will be faced in generating
mice models recapitulating the characteristics of one or
another of these diseases, and in devising individualized
therapeutic approaches.
Acknowledgements
We thank Dr Magalie Lecourtois for helping to prepare the review
and Tracey Avequin for editing the paper before submission.
Funding
Studies in our laboratory were supported by Inserm grants and by
G4 grants [contract grant number 2004/147/HP-UF R 809].
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Received 24 February 2012
doi:10.1042/BST20120045