C9orf72 Protein; C9orf72 protein, human; Proteins; Adult; Age of Onset; Aged; Aged, 80 and over; Alleles; Alzheimer Disease/genetics; Base Sequence; Chromosomes, Human, Pair 9/genetics; Cohort Studies; DNA Repeat Expansion; Europe/epidemiology; Finland/epidemiology; Frontotemporal Lobar Degeneration/epidemiology; Frontotemporal Lobar Degeneration/genetics; Genome-Wide Association Study/methods; Germany/epidemiology; Haplotypes; Humans; Middle Aged; Molecular Sequence Data; Prevalence; Proteins/genetics; Spain/epidemiology; Sweden/epidemiology; Genomic Instability; C9orf72; European Early-Onset Dementia consortium; FTLD; Intermediate alleles; Repeat expansion; Genetics; Genetics (clinical)
Résumé :
[en] We assessed the geographical distribution of C9orf72 G(4) C(2) expansions in a pan-European frontotemporal lobar degeneration (FTLD) cohort (n = 1,205), ascertained by the European Early-Onset Dementia (EOD) consortium. Next, we performed a meta-analysis of our data and that of other European studies, together 2,668 patients from 15 Western European countries. The frequency of the C9orf72 expansions in Western Europe was 9.98% in overall FTLD, with 18.52% in familial, and 6.26% in sporadic FTLD patients. Outliers were Finland and Sweden with overall frequencies of respectively 29.33% and 20.73%, but also Spain with 25.49%. In contrast, prevalence in Germany was limited to 4.82%. In addition, we studied the role of intermediate repeats (7-24 repeat units), which are strongly correlated with the risk haplotype, on disease and C9orf72 expression. In vitro reporter gene expression studies demonstrated significantly decreased transcriptional activity of C9orf72 with increasing number of normal repeat units, indicating that intermediate repeats might act as predisposing alleles and in favor of the loss-of-function disease mechanism. Further, we observed a significantly increased frequency of short indels in the GC-rich low complexity sequence adjacent to the G(4) C(2) repeat in C9orf72 expansion carriers (P < 0.001) with the most common indel creating one long contiguous imperfect G(4) C(2) repeat, which is likely more prone to replication slippage and pathological expansion.
Disciplines :
Neurologie
Auteur, co-auteur :
van der Zee, Julie ✱; Department of Molecular Genetics, VIB, Antwerp, Belgium
Gijselinck, Ilse ✱
Dillen, Lubina
Van Langenhove, Tim
Theuns, Jessie
Engelborghs, Sebastiaan
Philtjens, Stéphanie
Vandenbulcke, Mathieu
Sleegers, Kristel
Sieben, Anne
Bäumer, Veerle
Maes, Githa
Corsmit, Ellen
Borroni, Barbara
Padovani, Alessandro
Archetti, Silvana
Perneczky, Robert
Diehl-Schmid, Janine
de Mendonça, Alexandre
Miltenberger-Miltenyi, Gabriel
Pereira, Sónia
Pimentel, José
Nacmias, Benedetta
Bagnoli, Silvia
Sorbi, Sandro
Graff, Caroline
Chiang, Huei-Hsin
Westerlund, Marie
Sanchez-Valle, Raquel
Llado, Albert
Gelpi, Ellen
Santana, Isabel
Almeida, Maria Rosário
Santiago, Beatriz
Frisoni, Giovanni
Zanetti, Orazio
Bonvicini, Cristian
Synofzik, Matthis
Maetzler, Walter
Vom Hagen, Jennifer Müller
Schöls, Ludger
HENEKA, Michael ; Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Bonn, Germany ; German Center for Neurodegenerative Diseases (DZNE), University of Bonn, Bonn, Germany
Al-Sarraj S, King A, Troakes C, Smith B, Maekawa S, Bodi I, Rogelj B, Al-Chalabi A, Hortobagyi T, Shaw CE. 2011. p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS. Acta Neuropathol 122:691-702.
Arighi A, Fumagalli GG, Jacini F, Fenoglio C, Ghezzi L, Pietroboni AM, De RM, Serpente M, Ridolfi E, Bonsi R, Bresolin N, Scarpini E, et al. 2012. Early onset behavioral variant frontotemporal dementia due to the C9ORF72 hexanucleotide repeat expansion: psychiatric clinical presentations. J Alzheimers Dis 31:447-452.
Aziz NA, Jurgens CK, Landwehrmeyer GB, van Roon-Mom WM, van Ommen GJ, Stijnen T, Roos RA. 2009. Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease. Neurology 73:1280-1285.
Bigio EH. 2012. Motor neuron disease: the C9orf72 hexanucleotide repeat expansion in FTD and ALS. Nat Rev Neurol 8:249-250.
Boeve BF, Boylan KB, Graff-Radford NR, Dejesus-Hernandez M, Knopman DS, Pedraza O, Vemuri P, Jones D, Lowe V, Murray ME, Dickson DW, Josephs KA, et al. 2012. Characterization of frontotemporal dementia and/or amyotrophic lateral sclerosis associated with the GGGGCC repeat expansion in C9ORF72. Brain 135:765-783.
Boxer AL, Mackenzie IR, Boeve BF, Baker M, Seeley WW, Crook R, Feldman H, Hsiung GY, Rutherford N, Laluz V, Whitwell J, Foti D, et al. 2011. Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family. J Neurol Neurosurg Psychiatry 82:196-203.
Brock GJ, Anderson NH, Monckton DG. 1999. Cis-acting modifiers of expanded CAG/CTG triplet repeat expandability: associations with flanking GC content and proximity to CpG islands. Hum Mol Genet 8:1061-1067.
Chio A, Borghero G, Restagno G, Mora G, Drepper C, Traynor BJ, Sendtner M, Brunetti M, Ossola I, Calvo A, Pugliatti M, Sotgiu MA, et al. 2012. Clinical characteristics of patients with familial amyotrophic lateral sclerosis carrying the pathogenic GGGGCC hexanucleotide repeat expansion of C9ORF72. Brain 135:784-793.
Dejesus-Hernandez M, Mackenzie IR, Boeve C, Boxer AL, Baker M, Rutherford NJ, Nicholson AM, Finch NA, Flynn H, Adamson J, Kouri N, Wojtas A, et al. 2011. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245-256, doi:10.1016/j.neuron.2011.09.011.
Ferrari R, Mok K, Moreno JH, Cosentino S, Goldman J, Pietrini P, Mayeux R, Tierney MC, Kapogiannis D, Jicha GA, Murrell JR, Ghetti B, et al. 2012. Screening for C9ORF72 repeat expansion in FTLD. Neurobiol Aging 33:1850.
Gijselinck I, Engelborghs S, Maes G, Cuijt I, Peeters K, Mattheijssens M, Joris G, Cras P, Martin JJ, De Deyn PP, Kumar-Singh S, Van Broeckhoven C, et al. 2010. Identification of 2 Loci at chromosomes 9 and 14 in a multiplex family with frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Arch Neurol 67:606-616.
Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G, Janssens J, Bettens K, Van Cauwenberghe C, Pereson S, Engelborghs S, Sieben A, et al. 2012. 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 11:54-65.
Gunter C, Paradee W, Crawford DC, Meadows KA, Newman J, Kunst CB, Nelson DL, Schwartz C, Murray A, Macpherson JN, Sherman SL, Warren ST. 1998. Re-examination of factors associated with expansion of CGG repeats using a single nucleotide polymorphism in FMR1. Hum Mol Genet 7:1935-1946.
Hsiung GY, Dejesus-Hernandez M, Feldman HH, Sengdy P, Bouchard-Kerr P, Dwosh E, Butler R, Leung B, Fok A, Rutherford NJ, Baker M, Rademakers R, et al. 2012. Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain 135:709-722.
Kumps C, Van RN, Heyrman L, Goossens D, Del-Favero J, Noguera R, Vandesompele J, Speleman F, De PK. 2010. Multiplex Amplicon Quantification (MAQ), a fast and efficient method for the simultaneous detection of copy number alterations in neuroblastoma. BMC Genomics 11:298.
Kunst CB, Warren ST. 1994. Cryptic and polar variation of the fragile X repeat could result in predisposing normal alleles. Cell 77:853-861.
Laaksovirta H, Peuralinna T, Schymick JC, Scholz SW, Lai SL, Myllykangas L, Sulkava R, Jansson L, Hernandez DG, Gibbs JR, Nalls MA, Heckerman D, et al. 2010. Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study. Lancet Neurol 9:978-985.
Larsen LA, Armstrong JS, Gronskov K, Hjalgrim H, Macpherson JN, Brondum-Nielsen K, Hasholt L, Norgaard-Pedersen B, Vuust J. 2000. Haplotype and AGG-interspersion analysis of FMR1 (CGG)(n) alleles in the Danish population: implications for multiple mutational pathways towards fragile X alleles. Am J Med Genet 93:99-106.
Le Ber I, Camuzat A, Berger E, Hannequin D, Laquerriere A, Golfier V, Seilhean D, Viennet G, Couratier P, Verpillat P, Heath S, Camu W, et al. 2009. Chromosome 9p-linked families with frontotemporal dementia associated with motor neuron disease. Neurology 72:1669-1676.
Lindquist S, Duno M, Batbayli M, Puschmann A, Braendgaard H, Mardosiene S, Svenstrup K, Pinborg L, Vestergaard K, Hjermind L, Stokholm J, Andersen B, et al. 2012. Corticobasal and ataxia syndromes widen the spectrum of C9ORF72 hexanucleotide expansion disease. Clin Genet 9999.
Luty AA, Kwok JB, Thompson EM, Blumbergs P, Brooks WS, Loy CT, Dobson-Stone C, Panegyres PK, Hecker J, Nicholson GA, Halliday GM, Schofield PR. 2008. Pedigree with frontotemporal lobar degeneration-motor neuron disease and Tar DNA binding protein-43 positive neuropathology: genetic linkage to chromosome 9. BMC Neurol 8:32.
Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, Kovacs GG, Ghetti B, Halliday G, Holm IE, Ince PG, Kamphorst W, et al. 2010. Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 119:1-4.
Mahoney CJ, Beck J, Rohrer JD, Lashley T, Mok K, Shakespeare T, Yeatman T, Warrington EK, Schott JM, Fox NC, Rossor MN, Hardy J, et al. 2012. Frontotemporal dementia with the C9ORF72 hexanucleotide repeat expansion: clinical, neuroanatomical and neuropathological features. Brain 135:736-750.
Majounie E, Renton AE, Mok K, Dopper EG, Waite A, Rollinson S, Chio A, Restagno G, Nicolaou N, Simon-Sanchez J, Van Swieten JC, Abramzon Y, et al. 2012. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol 11:323-330.
Mok K, Traynor BJ, Schymick J, Tienari PJ, Laaksovirta H, Peuralinna T, Myllykangas L, Chio A, Shatunov A, Boeve BF, Boxer AL, Dejesus-Hernandez M, et al. 2011. The chromosome 9 ALS and FTD locus is probably derived from a single founder. Neurobiol Aging 33:e3-e8.
Morita M, Al Chalabi A, Andersen PM, Hosler B, Sapp P, Englund E, Mitchell JE, Habgood JJ, de Belleroche J, Xi J, Brown RH. 2006. A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 66:839-844.
Murray ME, Dejesus-Hernandez M, Rutherford NJ, Baker M, Duara R, Graff-Radford NR, Wszolek ZK, Ferman TJ, Josephs KA, Boylan KB, Rademakers R, Dickson DW. 2011. Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol 122:673-690.
Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, et al. 1998. Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:1546-1554.
Nestor CE, Monckton DG. 2011. Correlation of inter-locus polyglutamine toxicity with CAG*CTG triplet repeat expandability and flanking genomic DNA GC content. PLoS One 6:e28260.
Pamphlett R, Cheong PL, Trent RJ, Yu B. 2012. Transmission of C9orf72 hexanucleotide repeat expansions in sporadic amyotrophic lateral sclerosis: an Australian trio study. Neuroreport 23:556-559.
Pearson JP, Williams NM, Majounie E, Waite A, Stott J, Newsway V, Murray A, Hernandez D, Guerreiro R, Singleton AB, Neal J, Morris HR. 2011. Familial frontotemporal dementia with amyotrophic lateral sclerosis and a shared haplotype on chromosome 9p. J Neurol 258:647-655.
Renton AE, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs JR, Schymick JC, Laaksovirta H, van Swieten JC, Myllykangas L, Kalimo H, Paetau A, et al. 2011. A hexanucleotide repeat expansion in C9ORF72 Is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72:257-268, doi:10.1016/j.neuron.2011.09.010.
Rozen S, Skaletsky H. 2000. Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132:365-386.
Rutherford NJ, Zhang YJ, Baker M, Gass JM, Finch NA, Xu YF, Stewart H, Kelley BJ, Kuntz K, Crook RJ, Sreedharan J, Vance C, et al. 2008. Novel mutations in TARDBP (TDP-43) in patients with familial amyotrophic lateral sclerosis. PLoS Genet 4:e1000193.
Shatunov A, Mok K, Newhouse S, Weale ME, Smith B, Vance C, Johnson L, Veldink JH, van Es MA, van den Berg LH, Robberecht W, Van DP, et al. 2010. Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study. Lancet Neurol 9:986-994.
Simon-Sanchez J, Dopper EG, Cohn-Hokke PE, Hukema RK, Nicolaou N, Seelaar H, de Graaf JR, de KI, van Schoor NM, Deeg DJ, Smits M, Raaphorst J, et al. 2012. The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions. Brain 135:723-735.
Snowden JS, Rollinson S, Thompson JC, Harris JM, Stopford CL, Richardson AM, Jones M, Gerhard A, Davidson YS, Robinson A, Gibbons L, Hu Q, et al. 2012. Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations. Brain 135:693-708.
Stewart H, Rutherford NJ, Briemberg H, Krieger C, Cashman N, Fabros M, Baker M, Fok A, Dejesus-Hernandez M, Eisen A, Rademakers R, Mackenzie IR. 2012. Clinical and pathological features of amyotrophic lateral sclerosis caused by mutation in the C9ORF72 gene on chromosome 9p. Acta Neuropathol 123:409-417.
Troakes C, Maekawa S, Wijesekera L, Rogelj B, Siklos L, Bell C, Smith B, Newhouse S, Vance C, Johnson L, Hortobagyi T, Shatunov A, et al. 2011. An MND/ALS phenotype associated with C9orf72 repeat expansion: abundant p62-positive, TDP-43-negative inclusions in cerebral cortex, hippocampus and cerebellum but without associated cognitive decline. Neuropathology 32:505-514.
Valdmanis PN, Kabashi E, Dion PA, Rouleau GA. 2008. ALS predisposition modifiers: knock NOX, who's there? SOD1 mice still are. Eur J Hum Genet 16:140-142.
Van Deerlin VM, Sleiman PM, Martinez-Lage M, Chen-Plotkin A, Wang LS, Graff-Radford NR, Dickson DW, Rademakers R, Boeve BF, Grossman M, Arnold SE, Mann DM, et al. 2010. Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions. Nat Genet 42:234-239.
van Es MA, Veldink JH, Saris CG, Blauw HM, van Vught PW, Birve A, Lemmens R, Schelhaas HJ, Groen EJ, Huisman MH, Van Der Kooi AJ, De VM, et al. 2009. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet 41:1083-1087.
Van Langenhove T, Van Broeckhoven C, van der Zee J. 2012a. The molecular basis of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum. Ann Med. [Epub ahead of print.]
Van Langenhove T, van der Zee J, Gijselinck I, Engelborghs S, Vandenberghe R, Vandenbulcke M, De Bleeckere J, Sieben A, Versijpt J, Ivanoiu A, Deryck O, Willems C, et al. 2012b. Distinct clinical characteristics of C9orf72 expansion carriers compared to GRN, MAPT and non-mutation carriers in a Flanders-Belgian FTLD cohort. Arch Neurol [In press].
Vance C, Al Chalabi A, Ruddy D, Smith BN, Hu X, Sreedharan J, Siddique T, Schelhaas HJ, Kusters B, Troost D, Baas F, de Jong V, et al. 2006. Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. Brain 129:868-876.
Weckx S, Del Favero J, Rademakers R, Claes L, Cruts M, De Jonghe P, Van Broeckhoven C, De Rijk P. 2005. novoSNP, a novel computational tool for sequence variation discovery. Genome Res 15:436-442.
Whitwell JL, Weigand SD, Boeve BF, Senjem ML, Gunter JL, Dejesus-Hernandez M, Rutherford NJ, Baker M, Knopman DS, Wszolek ZK, Parisi JE, Dickson DW, et al. 2012. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics. Brain 135:794-806.
