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672 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 C 2012 Biochemical Society 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 C The C 2012 Biochemical Society Authors Journal compilation 673 674 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 C 2012 Biochemical Society 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]. References 1 Feuk, L., Carson, A.R. and Scherer, S.W. (2006) Structural variation in the human genome. Nat. Rev. Genet. 7, 85–97 2 Iafrate, A.J., Feuk, L., Rivera, M.N., Listewnik, M.L., Donahoe, P.K., Qi, Y., Scherer, S.W. and Lee, C. (2004) Detection of large-scale variation in the human genome. Nat. Genet. 36, 949–951 3 Sebat, J., Lakshmi, B., Troge, J., Alexander, J., Young, J., Lundin, P., Maner, S., Massa, H., Walker, M., Chi, M. et al. (2004) Large-scale copy number polymorphism in the human genome. Science 305, 525–528 4 Perry, G.H., Yang, F., Marques-Bonet, T., Murphy, C., Fitzgerald, T., Lee, A.S., Hyland, C., Stone, A.C., Hurles, M.E., Tyler-Smith, C. et al. (2008) Copy number variation and evolution in humans and chimpanzees. Genome Res. 18, 1698–1710 5 Redon, R., Ishikawa, S., Fitch, K.R., Feuk, L., Perry, G.H., Andrews, T.D., Fiegler, H., Shapero, M.H., Carson, A.R., Chen, W. et al. (2006) Global variation in copy number in the human genome. Nature 444, 444–454 6 Lee, J.A. and Lupski, J.R. (2006) Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders. Neuron 52, 103–121 7 Shchelochkov, O.A., Cheung, S.W. and Lupski, J.R. (2010) Genomic and clinical characteristics of microduplications in chromosome 17. Am. J. Med. Genet. A 152, 1101–1110 8 Lupski, J.R., Chance, P.F. and Garcia, C.A. (1993) Inherited primary peripheral neuropathies: molecular genetics and clinical implications of CMT1A and HNPP. JAMA, J. Am. Med. Assoc. 270, 2326–2330 9 Cruts, M., Rademakers, R., Gijselinck, I., van der Zee, J., Dermaut, B., de Pooter, T., de Rijk, P., Del-Favero, J. and van Broeckhoven, C. (2005) Genomic architecture of human 17q21 linked to frontotemporal dementia uncovers a highly homologous family of low-copy repeats in the tau region. Hum. Mol. Genet. 14, 1753–1762 10 Stefansson, H., Helgason, A., Thorleifsson, G., Steinthorsdottir, V., Masson, G., Barnard, J., Baker, A., Jonasdottir, A., Ingason, A., Gudnadottir, V.G. et al. (2005) A common inversion under selection in Europeans. Nat. Genet. 37, 129–137 11 Goode, B.L., Chau, M., Denis, P.E. and Feinstein, S.C. (2000) Structural and functional differences between 3-repeat and 4-repeat tau isoforms. Implications for normal tau function and the onset of neurodegenerative disease. J. Biol. Chem. 275, 38182–38189 12 Frank, S., Clavaguera, F. and Tolnay, M. (2008) Tauopathy models and human neuropathology: similarities and differences. Acta Neuropathol. 115, 39–53 13 Koolen, D.A., Vissers, L.E., Pfundt, R., de Leeuw, N., Knight, S.J., Regan, R., Kooy, R.F., Reyniers, E., Romano, C., Fichera, M. et al. (2006) A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat. Genet. 38, 999–1001 14 Shaw-Smith, C., Pittman, A.M., Willatt, L., Martin, H., Rickman, L., Gribble, S., Curley, R., Cumming, S., Dunn, C., Kalaitzopoulos, D. et al. (2006) Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nat. Genet. 38, 1032–1037 15 Dubourg, C., Sanlaville, D., Doco-Fenzy, M., Le Caignec,, C., Missirian, C., Jaillard, S., Schluth-Bolard, C., Landais, E., Boute, O., Philip, N. et al. (2011) Clinical and molecular characterization of 17q21.31 microdeletion syndrome in 14 French patients with mental retardation. Eur. J. Med. Genet. 54, 144–151 16 El Chehadeh-Djebbar, S., Callier, P., Masurel-Paulet, A., Bensignor, C., Mejean, N., Payet, M., Ragon, C., Durand, C., Marle, N., Mosca-Boidron, A.L. et al. (2011) 17q21.31 microdeletion in a patient with pituitary stalk interruption syndrome. Eur. J. Med. Genet. 54, 369–373 17 Kitsiou-Tzeli, S., Frysira, H., Giannikou, K., Syrmou, A., Kosma, K., Kakourou, G., Leze, E., Sofocleous, C., Kanavakis, E. and Tzetis, M. (2011) Microdeletion and microduplication 17q21.31 plus an additional CNV, in patients with intellectual disability, identified by array-CGH. Gene 492, 319–324 18 Kirchhoff, M., Bisgaard, A.M., Duno, M., Hansen, F.J. and Schwartz, M. (2007) A 17q21.31 microduplication, reciprocal to the newly described 17q21.31 microdeletion, in a girl with severe psychomotor developmental delay and dysmorphic craniofacial features. Eur. J. Med. Genet. 50, 256–263 19 Grisart, B., Willatt, L., Destree, A., Fryns, J.P., Rack, K., de Ravel, T., Rosenfeld, J., Vermeesch, J.R., Verellen-Dumoulin, C. and Sandford, R. (2009) 17q21.31 microduplication patients are characterised by behavioural problems and poor social interaction. J. Med. Genet. 46, 524–530 20 Guilmatre, A., Dubourg, C., Mosca, A.L., Legallic, S., Goldenberg, A., Drouin-Garraud, V., Layet, V., Rosier, A., Briault, S., Bonnet-Brilhault, F. et al. (2009) Recurrent rearrangements in synaptic and neurodevelopmental genes and shared biologic pathways in schizophrenia, autism, and mental retardation. Arch. Gen. Psychiatry 66, 947–956 21 Rovelet-Lecrux, A., Hannequin, D., Guillin, O., Legallic, S., Jurici, S., Wallon, D., Frebourg, T. and Campion, D. (2010) Frontotemporal dementia phenotype associated with MAPT gene duplication. J. Alzheimer’s Dis. 21, 897–902 22 Rovelet-Lecrux, A., Lecourtois, M., Thomas-Anterion, C., Le Ber, I., Brice, A., Frebourg, T., Hannequin, D. and Campion, D. (2009) Partial deletion of the MAPT gene: a novel mechanism of FTDP-17. Hum. Mutat. 30, E591–E602 23 Alonso, A.D., Grundke-Iqbal, I., Barra, H.S. and Iqbal, K. (1997) Abnormal phosphorylation of tau and the mechanism of Alzheimer neurofibrillary degeneration: sequestration of microtubule-associated proteins 1 and 2 and the disassembly of microtubules by the abnormal tau. Proc. Natl. Acad. Sci. U.S.A. 94, 298–303 24 Dawson, H.N., Ferreira, A., Eyster, M.V., Ghoshal, N., Binder, L.I. and Vitek, M.P. (2001) Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. J. Cell Sci. 114, 1179–1187 25 Harada, A., Oguchi, K., Okabe, S., Kuno, J., Terada, S., Ohshima, T., Sato-Yoshitake, R., Takei, Y., Noda, T. and Hirokawa, N. (1994) Altered microtubule organization in small-calibre axons of mice lacking tau protein. Nature 369, 488–491 C The C 2012 Biochemical Society Authors Journal compilation 675 676 Biochemical Society Transactions (2012) Volume 40, part 4 26 Sapir, T., Frotscher, M., Levy, T., Mandelkow, E.M. and Reiner, O. (2012) Tau’s role in the developing brain: implications for intellectual disability. Hum. Mol. Genet. 21, 1681–1692 27 Papaleo, F., Kitchener, P. and Contarino, A. (2007) Disruption of the CRF/CRF1 receptor stress system exacerbates the somatic signs of opiate withdrawal. Neuron 53, 577–589 28 Smith, G.W., Aubry, J.M., Dellu, F., Contarino, A., Bilezikjian, L.M., Gold, L.H., Chen, R., Marchuk, Y., Hauser, C., Bentley, C.A. et al. (1998) Corticotropin releasing factor receptor 1-deficient mice display decreased anxiety, impaired stress response, and aberrant neuroendocrine development. Neuron 20, 1093–1102 29 Jakel, S., Mingot, J.M., Schwarzmaier, P., Hartmann, E. and Gorlich, D. (2002) Importins fulfil a dual function as nuclear import receptors and cytoplasmic chaperones for exposed basic domains. EMBO J. 21, 377–386 30 Bosia, M., Buonocore, M., Guglielmino, C., Pirovano, A., Lorenzi, C., Marcone, A., Bramanti, P., Cappa, S.F., Aguglia, E., Smeraldi, E. and Cavallaro, R. (2011) Saitohin polymorphism and executive dysfunction in schizophrenia. Neurol. Sci., doi:10.1007/s10072–011-0893–9 31 Conrad, C., Vianna, C., Freeman, M. and Davies, P. (2002) A polymorphic gene nested within an intron of the tau gene: implications for Alzheimer’s disease. Proc. Natl. Acad. Sci. U.S.A. 99, 7751–7756 C The C 2012 Biochemical Society Authors Journal compilation 32 Levecque, C., Elbaz, A., Clavel, J., Vidal, J.S., Amouyel, P., Alperovitch, A., Tzourio, C. and Chartier-Harlin, M.C. (2004) Association of polymorphisms in the Tau and Saitohin genes with Parkinson’s disease. J. Neurol. Neurosurg. Psychiatry 75, 478–480 33 Gao, L., Tse, S.W., Conrad, C. and Andreadis, A. (2005) Saitohin, which is nested in the tau locus and confers allele-specific susceptibility to several neurodegenerative diseases, interacts with peroxiredoxin 6. J. Biol. Chem. 280, 39268–39272 34 Wang, Y., Gao, L., Conrad, C.G. and Andreadis, A. (2011) Saitohin, which is nested within the tau gene, interacts with tau and Abl and its human-specific allele influences Abl phosphorylation. J. Cell. Biochem. 112, 3482–3488 35 Li, B., Boast, S., de los Santos, K., Schieren, I., Quiroz, M., Teitelbaum, S.L., Tondravi, M.M. and Goff, S.P. (2000) Mice deficient in Abl are osteoporotic and have defects in osteoblast maturation. Nat. Genet. 24, 304–308 Received 24 February 2012 doi:10.1042/BST20120045