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Chapter 14 - Geneticsof frontotemporal dementia and related disorders

from Section 4 - Pathology and pathophysiology

Published online by Cambridge University Press:  05 May 2016

By
Marc Cruts  and
Christine Van Broeckhoven
Edited by
Bradford C. Dickerson
Bradford C. Dickerson
Affiliation:
Department of Neurology, Massachusetts General Hospital
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Hodges' Frontotemporal Dementia , pp. 185 - 196
Publisher: Cambridge University Press
Print publication year: 2016

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References

Sieben, A, Van Langenhove, T, Engelborghs, S, Martin, JJ, Boon, P, Cras, P, et al. The genetics and neuropathology of frontotemporal lobar degeneration. Acta Neuropathol 2012;124(3):353–72.Google Scholar
Mackenzie, IR, Neumann, M, Bigio, EH, Cairns, NJ, Alafuzoff, I, Kril, J, et al. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 2010;119(1):1–4.Google Scholar
Neumann, M, Sampathu, DM, Kwong, LK, Truax, AC, Micsenyi, MC, Chou, TT, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 2006;314(5796):130–3.Google Scholar
Arai, T, Hasegawa, M, Akiyama, H, Ikeda, K, Nonaka, T, Mori, H, et al. TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 2006;351(3):602–11.Google Scholar
Mackenzie, IR, Neumann, M, Baborie, A, Sampathu, DM, Du Plessis, D, Jaros, E, et al. A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 2011;122(1):111–13.Google Scholar
Neary, D, Snowden, J, Mann, D. Frontotemporal dementia. Lancet Neurol 2005;4(11):771–80.Google Scholar
Cruts, M, Theuns, J, Van Broeckhoven, C. Locus-specific mutation databases for neurodegenerative brain diseases. Hum Mutat 2012;33(9):1340–4.Google Scholar
Van Langenhove, T, van der Zee, J, Van Broeckhoven, C. The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum. Ann Med 2012;44(8):817–28.CrossRefGoogle ScholarPubMed
Van Deerlin, V, Sleiman, PM, Martinez-Lage, M, Chen-Plotkin, A, Wang, LS, Graff-Radford, NR, et al. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet 2010;42(3):234–9.Google Scholar
Foster, NL, Wilhelmsen, K, Sima, AA, Jones, MZ, D'Amato, CJ, Gilman, S, et al. Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Ann Neurol 1997;41(6):706–15.CrossRefGoogle ScholarPubMed
Hutton, M, Lendon, CL, Rizzu, P, Baker, M, Froelich, S, Houlden, H, et al. Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998;393(6686):702–5.Google Scholar
D'Souza, I, Schellenberg, GD. Tau exon 10 expression involves a bipartite intron 10 regulatory sequence and weak 5′ and 3′ splice sites. J Biol Chem 2002;277(29):26587–99.CrossRefGoogle ScholarPubMed
Rademakers, R, Cruts, M, Van Broeckhoven, C. The role of tau (MAPT) in frontotemporal dementia and related tauopathies. Hum Mutat 2004;24(4):277–95.Google Scholar
Cruts, M, Van Broeckhoven, C. Loss of progranulin function in frontotemporal lobar degeneration. Trends Genet 2008;24(4):186–94.Google Scholar
Josephs, KA, Hodges, JR, Snowden, JS, Mackenzie, IR, Neumann, M, Mann, DM, et al. Neuropathological background of phenotypical variability in frontotemporal dementia. Acta Neuropathol 2011;122(2):137–53.Google Scholar
Baker, M, Mackenzie, IR, Pickering-Brown, SM, Gass, J, Rademakers, R, Lindholm, C, et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006;442(7105):916–19.Google Scholar
Cruts, M, Gijselinck, I, van der Zee, J, Engelborghs, S, Wils, H, Pirici, D, et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 2006;442(7105):920–4.Google Scholar
Kleinberger, G, Capell, A, Haass, C, Van Broeckhoven, C. Mechanisms of granulin deficiency: lessons from cellular and animal models. Mol Neurobiol 2013;47(1):337–60.CrossRefGoogle ScholarPubMed
Brouwers, N, Sleegers, K, Engelborghs, S, Maurer-Stroh, S, Gijselinck, I, van der Zee, J, et al. Genetic variability in progranulin contributes to risk for clinically diagnosed Alzheimer disease. Neurology 2008;71(9):656–64.Google Scholar
Sleegers, K, Brouwers, N, Van Broeckhoven, C. Role of progranulin as a biomarker for Alzheimer's disease. Biomark Med 2010;4(1):37–50.Google Scholar
Sleegers, K, Brouwers, N, Maurer-Stroh, S, van Es, MA, Van Damme, P, Van Vught, PW, et al. Progranulin genetic variability contributes to amyotrophic lateral sclerosis. Neurology 2008;71(4):253–9.Google Scholar
Rohrer, JD, Warren, JD. Phenotypic signatures of genetic frontotemporal dementia. Curr Opin Neurol 2011;24(6):542–9.Google Scholar
Le Ber, I, Camuzat, A, Hannequin, D, Pasquier, F, Guedj, E, Rovelet-Lecrux, A, et al. Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study. Brain 2008;131(Pt 3):732–46.Google Scholar
Brouwers, N, Nuytemans, K, van der Zee, J, Gijselinck, I, Engelborghs, S, Theuns, J, et al. Alzheimer and Parkinson diagnoses in progranulin null mutation carriers in an extended founder family. Arch Neurol 2007;64(10):1436–46.Google Scholar
Chen-Plotkin, AS, Martinez-Lage, M, Sleiman, PM, Hu, W, Greene, R, Wood, EM, et al. Genetic and clinical features of progranulin-associated frontotemporal lobar degeneration. Arch Neurol 2011;68(4):488–97.Google Scholar
Rademakers, R, Baker, M, Gass, J, Adamson, J, Huey, ED, Momeni, P, et al. Phenotypic variability associated with progranulin haploinsufficiency in patients with the common 1477C→T (Arg493X) mutation: an international initiative. Lancet Neurol 2007;6(10):857–68.Google Scholar
Vance, C, Al Chalabi, A, Ruddy, D, Smith, BN, Hu, X, Sreedharan, J, et al. Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2–21.3. Brain 2006;129(Pt 4):868–76.Google Scholar
Morita, M, Al Chalabi, A, Andersen, PM, Hosler, B, Sapp, P, Englund, E, et al. A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 2006;66(6):839–44.Google Scholar
Laaksovirta, H, Peuralinna, T, Schymick, JC, Scholz, SW, Lai, SL, Myllykangas, L, et al. Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Lancet Neurol 2010;9(10):978–85.Google Scholar
DeJesus-Hernandez, M, Mackenzie, IR, Boeve, BF, Boxer, AL, Baker, M, Rutherford, NJ, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011;72(2):245–56.CrossRefGoogle ScholarPubMed
Renton, AE, Majounie, E, Waite, A, Simon-Sanchez, J, Rollinson, S, Gibbs, JR, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 2011;72(2):257–68.Google Scholar
Gijselinck, I, Van Langenhove, T, van der Zee, J, Sleegers, K, Philtjens, S, Kleinberger, G, et al. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol 2012;11(1):54–65.Google Scholar
Cruts, M, Gijselinck, I, Van Langenhove, T, van der Zee, J, Van Broeckhoven, C. Current insights into the C9orf72 repeat expansion diseases of the FTLD/ALS spectrum. Trends Neurosci 2013;36(8):450–9.CrossRefGoogle ScholarPubMed
Majounie, E, Renton, AE, Mok, K, Dopper, EG, Waite, A, Rollinson, S, et al. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol 2012;11(4):323–30.Google Scholar
Smith, BN, Newhouse, S, Shatunov, A, Vance, C, Topp, S, Johnson, L, et al. The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder. Eur J Hum Genet 2013;21(1):102–8.Google Scholar
Beck, J, Poulter, M, Hensman, D, Rohrer, JD, Mahoney, CJ, Adamson, G, et al. Large C9orf72 hexanucleotide repeat expansions are seen in multiple neurodegenerative syndromes and are more frequent than expected in the UK population. Am J Hum Genet 2013;92(3):345–53.Google Scholar
Abel, O, Powell, JF, Andersen, PM, Al-Chalabi, A. ALSoD: a user-friendly online bioinformatics tool for amyotrophic lateral sclerosis genetics. Hum Mutat 2012;33(9):1345–51.Google Scholar
Mackenzie, IR, Frick, P, Neumann, M. The neuropathology associated with repeat expansions in the C9ORF72 gene. Acta Neuropathol 2014;127(3):347–57.Google Scholar
Mori, K, Lammich, S, Mackenzie, IR, Forne, I, Zilow, S, Kretzschmar, H, et al. hnRNP A3 binds to GGGGCC repeats and is a constituent of p62-positive/TDP43-negative inclusions in the hippocampus of patients with C9orf72 mutations. Acta Neuropathol 2013;125(3):413–23.Google Scholar
Mori, K, Weng, SM, Arzberger, T, May, S, Rentzsch, K, Kremmer, E, et al. The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science 2013;339(6125):1335–8.Google Scholar
Snowden, JS, Rollinson, S, Thompson, JC, Harris, JM, Stopford, CL, Richardson, AM, et al. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 2012;135(Pt 3):693–708.Google Scholar
Murray, ME, DeJesus-Hernandez, M, Rutherford, NJ, Baker, M, Duara, R, Graff-Radford, NR, et al. Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol 2011;122(6):673–90.Google Scholar
Van Langenhove, T, van der Zee, J, Gijselinck, I, Engelborghs, S, Vandenberghe, R, Vandenbulcke, M, et al. Distinct clinical characteristics of C9orf72 expansion carriers compared with GRN, MAPT, and nonmutation carriers in a Flanders-Belgian FTLD cohort. JAMA Neurol 2013;70(3):365–73.Google Scholar
Boeve, BF, Boylan, KB, Graff-Radford, NR, DeJesus-Hernandez, M, Knopman, DS, Pedraza, O, et al. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 2012;135(Pt 3):765–83.Google Scholar
Watts, GD, Wymer, J, Kovach, MJ, Mehta, SG, Mumm, S, Darvish, D, et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat Genet 2004;36(4):377–81.Google Scholar
Weihl, CC, Pestronk, A, Kimonis, VE. Valosin-containing protein disease: inclusion body myopathy with Paget's disease of the bone and fronto-temporal dementia. Neuromuscul Disord 2009;19(5):308–15.CrossRefGoogle ScholarPubMed
Dai, RM, Li, CC. Valosin-containing protein is a multi-ubiquitin chain-targeting factor required in ubiquitin-proteasome degradation. Nat Cell Biol 2001;3(8):740–4.Google Scholar
Ju, JS, Weihl, CC. p97/VCP at the intersection of the autophagy and the ubiquitin proteasome system. Autophagy 2010;6(2):283–5.Google Scholar
Schroder, R, Watts, GD, Mehta, SG, Evert, BO, Broich, P, Fliessbach, K, et al. Mutant valosin-containing protein causes a novel type of frontotemporal dementia. Ann Neurol 2005;57(3):457–61.Google Scholar
Weihl, CC. Valosin containing protein associated fronto-temporal lobar degeneration: clinical presentation, pathologic features and pathogenesis. Curr Alzheimer Res 2011;8(3):252–60.CrossRefGoogle ScholarPubMed
Johnson, JO, Mandrioli, J, Benatar, M, Abramzon, Y, Van Deerlin, VM, Trojanowski, JQ, et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 2010;68(5):857–64.Google Scholar
Skibinski, G, Parkinson, NJ, Brown, JM, Chakrabarti, L, Lloyd, SL, Hummerich, H, et al. Mutations in the endosomal ESCRTIII-complex subunit CHMP2B in frontotemporal dementia. Nat Genet 2005;37(8):806–8.Google Scholar
van der Zee, J, Urwin, H, Engelborghs, S, Bruyland, M, Vandenberghe, R, Dermaut, B, et al. CHMP2B C-truncating mutations in frontotemporal lobar degeneration are associated with an aberrant endosomal phenotype in vitro. Hum Mol Genet 2008;17(2):313–22.Google Scholar
Urwin, H, Authier, A, Nielsen, JE, Metcalf, D, Powell, C, Froud, K, et al. Disruption of endocytic trafficking in frontotemporal dementia with CHMP2B mutations. Hum Mol Genet 2010;19(11):2228–38.Google Scholar
Cox, LE, Ferraiuolo, L, Goodall, EF, Heath, PR, Higginbottom, A, Mortiboys, H, et al. Mutations in CHMP2B in lower motor neuron predominant amyotrophic lateral sclerosis (ALS). PLoS One 2010;5(3):e9872.Google Scholar
Isaacs, AM, Johannsen, P, Holm, I, Nielsen, JE. Frontotemporal dementia caused by CHMP2B mutations. Curr Alzheimer Res 2011;8(3):246–51.Google Scholar
Borroni, B, Bonvicini, C, Alberici, A, Buratti, E, Agosti, C, Archetti, S, et al. Mutation within TARDBP leads to frontotemporal dementia without motor neuron disease. Hum Mutat 2009;30(11):E974–83.CrossRefGoogle ScholarPubMed
Kwiatkowski, TJ Jr., Bosco, DA, Leclerc, AL, Tamrazian, E, Vanderburg, CR, Russ, C, et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 2009;323(5918):1205–8.Google Scholar
Van Langenhove, T, van der Zee, J, Sleegers, K, Engelborghs, S, Vandenberghe, R, Gijselinck, I, et al. Genetic contribution of FUS to frontotemporal lobar degeneration. Neurology 2010;74(5):366–71.Google Scholar
Mackenzie, IR, Munoz, DG, Kusaka, H, Yokota, O, Ishihara, K, Roeber, S, et al. Distinct pathological subtypes of FTLD-FUS. Acta Neuropathol 2011;121(2):207–18.Google Scholar
Lashley, T, Rohrer, JD, Bandopadhyay, R, Fry, C, Ahmed, Z, Isaacs, AM, et al. A comparative clinical, pathological, biochemical and genetic study of fused in sarcoma proteinopathies. Brain 2011;134(Pt 9):2548–64.CrossRefGoogle ScholarPubMed
van der Zee, J, Van Broeckhoven, C. TMEM106B a novel risk factor for frontotemporal lobar degeneration. J Mol Neurosci 2011;45(3):516–21.Google Scholar
van der Zee, J, Van Langenhove, T, Kleinberger, G, Sleegers, K, Engelborghs, S, Vandenberghe, R, et al. TMEM106B is associated with frontotemporal lobar degeneration in a clinically diagnosed patient cohort. Brain 2011;134(3):808–15.Google Scholar
Cruchaga, C, Graff, C, Chiang, HH, Wang, J, Hinrichs, AL, Spiegel, N, et al. Association of TMEM106B gene polymorphism with age at onset in granulin mutation carriers and plasma granulin protein levels. Arch Neurol 2011;68(5):581–6.Google Scholar
Premi, E, Formenti, A, Gazzina, S, Archetti, S, Gasparotti, R, Padovani, A, et al. Effect of TMEM106B polymorphism on functional network connectivity in asymptomatic GRN mutation carriers. JAMA Neurol 2014;71(2):216–21.Google Scholar
Vass, R, Ashbridge, E, Geser, F, Hu, WT, Grossman, M, Clay-Falcone, D, et al. Risk genotypes at TMEM106B are associated with cognitive impairment in amyotrophic lateral sclerosis. Acta Neuropathol 2011;121(3):373–80.Google Scholar
van Blitterswijk, M, Mullen, B, Nicholson, AM, Bieniek, KF, Heckman, MG, Baker, MC, et al. TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia. Acta Neuropathol 2014;127(3):397–406.Google Scholar
Gallagher, MD, Suh, E, Grossman, M, Elman, L, McCluskey, L, van Swieten, JC, et al. TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions. Acta Neuropathol 2014;127(3):407–18.Google Scholar
Lang, CM, Fellerer, K, Schwenk, BM, Kuhn, PH, Kremmer, E, Edbauer, D, et al. Membrane orientation and subcellular localization of transmembrane protein 106B (TMEM106B), a major risk factor for frontotemporal lobar degeneration. J Biol Chem 2012;287(23):19355–65.Google Scholar
Brady, OA, Zheng, Y, Murphy, K, Huang, M, Hu, F. The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function. Hum Mol Genet 2013;22(4):685–95.CrossRefGoogle ScholarPubMed
Schwenk, BM, Lang, CM, Hogl, S, Tahirovic, S, Orozco, D, Rentzsch, K, et al. The FTLD risk factor TMEM106B and MAP6 control dendritic trafficking of lysosomes. EMBO J 2014;33(5):450–67.Google Scholar
Cruts, M, Rademakers, R, Gijselinck, I, van der Zee, J, Dermaut, B, De Pooter, T, et al. 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 2005;14(13):1753–62.Google Scholar
Rademakers, R, Melquist, S, Cruts, M, Theuns, J, Del Favero, J, Poorkaj, P, et al. High-density SNP haplotyping suggests altered regulation of tau gene expression in progressive supranuclear palsy. Hum Mol Genet 2005;14(21):3281–92.Google Scholar
Hoglinger, GU, Melhem, NM, Dickson, DW, Sleiman, PM, Wang, LS, Klei, L, et al. Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 2011;43(7):699–705.CrossRefGoogle ScholarPubMed
Rademakers, R, Eriksen, JL, Baker, M, Robinson, T, Ahmed, Z, Lincoln, SJ, et al. Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia. Hum Mol Genet 2008;17(23):3631–42.Google Scholar
Galimberti, D, Fenoglio, C, Cortini, F, Serpente, M, Venturelli, E, Villa, C, et al. GRN variability contributes to sporadic frontotemporal lobar degeneration. J Alzheimers Dis 2010;19(1):171–7.Google Scholar
Banzhaf-Strathmann, J, Claus, R, Mucke, O, Rentzsch, K, van der Zee, J, Engelborghs, S, et al. Promoter DNA methylation regulates progranulin expression and is altered in FTLD. Acta Neuropathol Commun 2013;1(1):16.Google Scholar
van der Zee, J, Gijselinck, I, Dillen, L, Van Langenhove, T, Theuns, J, Engelborghs, S, et al. A pan-European study of the C9orf72 repeat associated with FTLD: geographic prevalence, genomic instability and intermediate repeats. Hum Mutat 2013;34(2):363–73.Google Scholar
Janssens, J, Van Broeckhoven, C. Pathological mechanisms underlying TDP-43 driven neurodegeneration in FTLD-ALS spectrum disorders. Hum Mol Genet 2013;22(R1):R77–7.Google Scholar
Gijselinck, I, Van Broeckhoven, C, Cruts, M. Granulin mutations associated with frontotemporal lobar degeneration and related disorders: an update. Hum Mutat 2008;29(12):1373–86.Google Scholar
Cirulli, ET, Lasseigne, BN, Petrovski, S, Sapp, PC, Dion, PA, Leblond, CS, et al. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways. Science 2015;347(6229):1436–41.Google Scholar
Freischmidt, A, Wieland, T, Richter, B, Ruf, W, Schaeffer, V, Muller, K, et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat Neurosci 2015;18(5):631–6.Google Scholar
Pottier, C, Bieniek, KF, Finch, N, van de Vorst, M, Baker, M, Perkersen, R, et al. Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease. Acta Neuropathol 2015;130(1):77–92.Google Scholar
Gijselinck, I, Van Mossevelde, S, van der Zee, J, Sieben, A, Philtjens, S, Heeman, B, et al. Loss of TBK1 is a frequent cause of frontotemporal dementia in a Belgian cohort. Neurology 2015. In press.Google Scholar

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