ALS: Recent Developments from Genetics Studies

Current Neurology and Neuroscience Reports

Volumn 16, Issue 6, 2016, Pages

  Therrien, Martine ^a   Dion, Patrick A ^b   Rouleau, Guy A ^b  

^a UNIVERSITÉ DE MONTRÉAL   (Canada)

^b MCGILL UNIVERSITY   (Canada)

Author keywords

ALS; Genetics; Motor neuron diseases

Indexed keywords

MATR3 PROTEIN; RNA BINDING PROTEIN; TBK1 PROTEIN; UNCLASSIFIED DRUG; C9ORF72 PROTEIN, HUMAN; CHCHD10 PROTEIN, HUMAN; MATR3 PROTEIN, HUMAN; MITOCHONDRIAL PROTEIN; NUCLEAR MATRIX PROTEIN; PROTEIN; PROTEIN SERINE THREONINE KINASE; TBK1 PROTEIN, HUMAN;

AMYOTROPHIC LATERAL SCLEROSIS; AUTOPHAGY; C9ORF72 GENE; CHCHD10 GENE; GENE; GENE FREQUENCY; GENE SEQUENCE; GENETIC ANALYSIS; GENETIC ASSOCIATION; GENETIC COUNSELING; GENETIC RISK; GENETIC SCREENING; GENETIC SUSCEPTIBILITY; GENETIC VARIABILITY; HUMAN; MUTATIONAL ANALYSIS; NERVOUS SYSTEM INFLAMMATION; PATHOGENESIS; REVIEW; SOD1 GENE; ANIMAL; GENETICS; MUTATION;

AMYOTROPHIC LATERAL SCLEROSIS; ANIMALS; HUMANS; MITOCHONDRIAL PROTEINS; MUTATION; NUCLEAR MATRIX-ASSOCIATED PROTEINS; PROTEIN-SERINE-THREONINE KINASES; PROTEINS; RNA-BINDING PROTEINS;

EID: 84964523724     PISSN: 15284042     EISSN: 15346293     Source Type: Journal    
DOI: 10.1007/s11910-016-0658-1     Document Type: Review

References (101)

1. Robberecht W, Philips T. The changing scene of amyotrophic lateral sclerosis. Nat Rev Neurosci. 2013;14:248–64.
2. Lattante S, Ciura S, Rouleau GA, Kabashi E. Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD). Trends Genet. 2015;31:263–73.
3. Ittner LM, Halliday GM, Kril JJ, Götz J, Hodges JR, Kiernan MC. FTD and ALS--translating mouse studies into clinical trials. Nat Rev Neurol. 2015;11:360–6.
4. Al-Chalabi A, Visscher PM. Motor neuron disease: common genetic variants and the heritability of ALS. Nat Rev Neurol. 2014;10:549–50.
5. Guerreiro R, Brás J, Hardy J. SnapShot: Genetics of ALS and FTD. Cell. 2015;160:798–798.e1.
6. Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature. 1993;362:59–62.
7. Bowling AC, Schulz JB, Brown RH, Beal MF. Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis. J Neurochem. 1993;61:2322–5.
8. 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;314:130–3.
9. Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C, et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet. 2008;40:572–4.
10. Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science. 2008;319:1668–72.
11. Al-Chalabi A, Jones A, Troakes C, King A, Al-Sarraj S, den Berg LH. The genetics and neuropathology of amyotrophic lateral sclerosis. Acta Neuropathol. 2012;124:339–52.
12. Renton AE, Chiò A, Traynor BJ. State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci. 2014;17:17–23.
13. Pickles S, Vande Velde C. Misfolded SOD1 and ALS: zeroing in on mitochondria. Amyotroph Lateral Scler. 2012;13:333–40.
14. Tafuri F, Ronchi D, Magri F, Comi GP, Corti S. SOD1 misplacing and mitochondrial dysfunction in amyotrophic lateral sclerosis pathogenesis. Front Cell Neurosci. 2015;9:336.
15. Lagier-Tourenne C, Polymenidou M, Cleveland DW. TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Hum Mol Genet. 2010;19:R46–64.
16. Vance C, Rogelj B, Hortobágyi T, De Vos KJ, Nishimura AL, Sreedharan J, et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009;323:1208–11.
17. Kwiatkowski TJ, 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;323:1205–8.
18. Fontana F, Siva K, Denti MA. A network of RNA and protein interactions in Fronto Temporal Dementia. Front Mol Neurosci. 2015;8:9.
19. Ling S-C, Polymenidou M, Cleveland DW. Converging mechanisms in ALS and FTD: disrupted RNA and protein homeostasis. Neuron. 2013;79:416–38.
20. Kim HJ, Kim NC, Wang Y-D, Scarborough EA, Moore J, Diaz Z, et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature. 2013;495:467–73.
21. Chen Y-Z, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet. 2004;74:1128–35.
22. Turner MR, Hardiman O, Benatar M, Brooks BR, Chiò A, de Carvalho M, et al. Controversies and priorities in amyotrophic lateral sclerosis. Lancet Neurol. 2013;12:310–22.
23. Schipper LJ, Raaphorst J, Aronica E, Baas F, de Haan R, de Visser M, et al. Prevalence of brain and spinal cord inclusions, including dipeptide repeat proteins, in patients with the C9ORF72 hexanucleotide repeat expansion: a systematic neuropathological review. Neuropathol Appl Neurobiol. 2015. doi:10.1111/nan.12284.
24. Patel A, Lee HO, Jawerth L, Maharana S, Jahnel M, Hein MY, et al. A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation. Cell. 2015;162:1066–77. Patel et al. reported how the prion domain of FUS forms liquid droplets that initiate aggregates formation and how mutant FUS protein could accelerate this process.
25. Kato M, Han TW, Xie S, Shi K, Du X, Wu LC, et al. Cell-free formation of RNA granules: low complexity sequence domains form dynamic fibers within hydrogels. Cell. 2012;149:753–67.
26. Majcher V, Goode A, James V, Layfield R. Autophagy receptor defects and ALS-FTLD. Mol Cell Neurosci. 2015;66:43–52.
27. Rohrer JD, Isaacs AM, Mizielinska S, Mead S, Lashley T, Wray S, et al. C9orf72 expansions in frontotemporal dementia and amyotrophic lateral sclerosis. Lancet Neurol. 2015;14:291–301.
28. 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;72:245–56.
29. Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, et al. A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD. Neuron. 2011;72:257–68.
30. Gómez-Tortosa E, Gallego J, Guerrero-López R, Marcos A, Gil-Neciga E, Sainz MJ, et al. C9ORF72 hexanucleotide expansions of 20-22 repeats are associated with frontotemporal deterioration. Neurology. 2013;80:366–70. Gómez-Tortosa et al. were the first to suggest that intermediate repeat of GGGGCC in C9ORF72 could also be pathogenic.
31. Byrne S, Heverin M, Elamin M, Walsh C, Hardiman O. Intermediate repeat expansion length in C9orf72 may be pathological in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2014;15:148–50.
32. Cooper-Knock J, Higginbottom A, Connor-Robson N, Bayatti N, Bury JJ, Kirby J, et al. C9ORF72 transcription in a frontotemporal dementia case with two expanded alleles. Neurology. 2013;81:1719–21.
33. Fratta P, Poulter M, Lashley T, Rohrer JD, Polke JM, Beck J, et al. Homozygosity for the C9orf72 GGGGCC repeat expansion in frontotemporal dementia. Acta Neuropathol. 2013;126:401–9.
34. La Spada AR, Paulson HL, Fischbeck KH. Trinucleotide repeat expansion in neurological disease. Ann Neurol. 1994;36:814–22.
35. Akimoto C, Volk AE, van Blitterswijk M, Van den Broeck M, Leblond CS, Lumbroso S, et al. A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories. J Med Genet. 2014;51:419–24.
36. Dols-Icardo O, García-Redondo A, Rojas-García R, Sanchez-Valle R, Noguera A, Gómez-Tortosa E, et al. Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia. Hum Mol Genet. 2014;23:749–54.
37. van Blitterswijk M, DeJesus-Hernandez M, Niemantsverdriet E, Murray ME, Heckman MG, Diehl NN, et al. Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions: a cross-sectional cohort study. Lancet Neurol. 2013;12:978–88.
38. 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;11:54–65.
39. Belzil VV, Bauer PO, Prudencio M, Gendron TF, Stetler CT, Yan IK, et al. Reduced C9orf72 gene expression in c9FTD/ALS is caused by histone trimethylation, an epigenetic event detectable in blood. Acta Neuropathol. 2013;126:895–905.
40. Suzuki N, Maroof AM, Merkle FT, Koszka K, Intoh A, Armstrong I, et al. The mouse C9ORF72 ortholog is enriched in neurons known to degenerate in ALS and FTD. Nat Neurosci. 2013;16:1725–7.
41. Xiao S, MacNair L, McGoldrick P, McKeever PM, McLean JR, Zhang M, et al. Isoform-specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis. Ann Neurol. 2015;78:568–83.
42. Levine TP, Daniels RD, Gatta AT, Wong LH, Hayes MJ. The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs. Bioinformatics. 2013;29:499–503. Levine et al. reported a prospective in silico study to propose what could be a cellular function of the product encoded by C9ORF72.
43. Zhang D, Iyer LM, He F, Aravind L. Discovery of novel DENN proteins: implications for the evolution of eukaryotic intracellular membrane structures and human disease. Front Genet. 2012;3:283.
44. Chaineau M, Ioannou MS, McPherson PS. Rab35: GEFs, GAPs and effectors. Traffic. 2013;14:1109–17.
45. Farg MA, Sundaramoorthy V, Sultana JM, Yang S, Atkinson RAK, Levina V, et al. C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Hum Mol Genet. 2014;23:3579–95.
46. Ivanov P, O'Day E, Emara MM, Wagner G, Lieberman J, Anderson P. G-quadruplex structures contribute to the neuroprotective effects of angiogenin-induced tRNA fragments. Proc Natl Acad Sci. 2014;111:18201–6.
47. Rossi S, Serrano A, Gerbino V, Giorgi A, Di Francesco L, Nencini M, et al. Nuclear accumulation of mRNAs underlies G4C2-repeat-induced translational repression in a cellular model of C9orf72 ALS. J Cell Sci. 2015;128:1787–99.
48. Freibaum BD, Lu Y, Lopez-Gonzalez R, Kim NC, Almeida S, Lee K-H, et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015;525:129–33.
49. Jovičić A, Mertens J, Boeynaems S, Bogaert E, Chai N, Yamada SB, et al. Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci. 2015;18:1226–9.
50. Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015;525:56–61. References 48-50 describe the use of various model organisms and patient material to establish nucleoplasmic shuttling impairments when C9ORF72 mRNAs contain expanded GGGGCC repeat.
51. Kaneb HM, Folkmann AW, Belzil VV, Jao L-E, Leblond CS, Girard SL, et al. Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis. Hum Mol Genet. 2015;24:1363–73.
52. Bannwarth S, Ait-El-Mkadem S, Chaussenot A, Genin EC, Lacas-Gervais S, Fragaki K, et al. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain. 2014;137:2329–45. Bannwarth et al were the first to link CHCHD10 with ALS and FTD. Many mutations in patients were identified and mitochondrial abnormalities were confirmed in patient cells.
53. Chaussenot A, Le Ber I, Ait-El-Mkadem S, Camuzat A, de Septenville A, Bannwarth S, et al. Screening of CHCHD10 in a French cohort confirms the involvement of this gene in frontotemporal dementia with amyotrophic lateral sclerosis patients. Neurobiol Aging. 2014;35:2884.e1–4.
54. Chiò A, Mora G, Sabatelli M, Caponnetto C, Traynor BJ, Johnson JO, et al. CHCH10 mutations in an Italian cohort of familial and sporadic amyotrophic lateral sclerosis patients. Neurobiol Aging. 2015;1767(36):e3–6.
55. Johnson JO, Glynn SM, Gibbs JR, Nalls MA, Sabatelli M, Restagno G, et al. Mutations in the CHCHD10 gene are a common cause of familial amyotrophic lateral sclerosis. Brain. 2014;137:e311–1.
56. Dols-Icardo O, Nebot I, Gorostidi A, Ortega-Cubero S, Hernández I, Rojas-García R, et al. Analysis of the CHCHD10 gene in patients with frontotemporal dementia and amyotrophic lateral sclerosis from Spain. Brain. 2015;138:e400.
57. Pasanen P, Myllykangas L, Pöyhönen M, Kiuru-Enari S, Tienari PJ, Laaksovirta H, et al. Intrafamilial clinical variability in individuals carrying the CHCHD10 mutation Gly66Val. Acta Neurol Scand. 2016;133(5):361–6.
58. Zhang M, Xi Z, Zinman L, Bruni AC, Maletta RG, Curcio SAM, et al. Mutation analysis of CHCHD10 in different neurodegenerative diseases. Brain. 2015;138:e380.
59. Müller K, Andersen PM, Hübers A, Marroquin N, Volk AE, Danzer KM, et al. Two novel mutations in conserved codons indicate that CHCHD10 is a gene associated with motor neuron disease. Brain. 2014;137:e309–9.
60. Marroquin N, Stranz S, Müller K, Wieland T, Ruf WP, Brockmann SJ, et al. Screening for CHCHD10 mutations in a large cohort of sporadic ALS patients: no evidence for pathogenicity of the p.P34S variant. Brain. 2015;139(Pt 2):e8.
61. Wong CH, Topp S, Gkazi A-S, Troakes C, Miller JW, de Majo M, et al. The CHCHD10 P34S variant is not associated with ALS in a UK cohort of familial and sporadic patients. Neurobiol Aging. 2015;36:2908.e17–8.
62. Abdelkarim S, Morgan S, Plagnol V, Lu C-H, Adamson G, Howard R, et al. CHCHD10 Pro34Ser is not a highly penetrant pathogenic variant for amyotrophic lateral sclerosis and frontotemporal dementia. Brain. 2016;139:e9. doi:10.1093/brain/awv223.
63. Ronchi D, Riboldi G, Del Bo R, Ticozzi N, Scarlato M, Galimberti D, et al. CHCHD10 mutations in Italian patients with sporadic amyotrophic lateral sclerosis. Brain. 2015;138:e372–2.
64. Dobson-Stone C, Shaw AD, Hallupp M, Bartley L, McCann H, Brooks WS, et al. Is CHCHD10 Pro34Ser pathogenic for frontotemporal dementia and amyotrophic lateral sclerosis? Brain. 2015;138:e385–5.
65. Kurzwelly D, Krüger S, Biskup S, Heneka MT. A distinct clinical phenotype in a German kindred with motor neuron disease carrying a CHCHD10 mutation. Brain. 2015;138:e376–6.
66. Depreux FF, Puckelwartz MJ, Augustynowicz A, Wolfgeher D, Labno CM, Pierre-Louis D, et al. Disruption of the lamin A and matrin-3 interaction by myopathic LMNA mutations. Hum Mol Genet. 2015;24:4284–95.
67. Feit H, Silbergleit A, Schneider LB, Gutierrez JA, Fitoussi RP, Réyès C, et al. Vocal cord and pharyngeal weakness with autosomal dominant distal myopathy: clinical description and gene localization to 5q31. Am J Hum Genet. 1998;63:1732–42.
68. Senderek J, Garvey SM, Krieger M, Guergueltcheva V, Urtizberea A, Roos A, et al. Autosomal-dominant distal myopathy associated with a recurrent missense mutation in the gene encoding the nuclear matrix protein, matrin 3. Am J Hum Genet. 2009;84:511–8.
69. Müller TJ, Kraya T, Stoltenburg-Didinger G, Hanisch F, Kornhuber M, Stoevesandt D, et al. Phenotype of matrin-3-related distal myopathy in 16 German patients. Ann Neurol. 2014;76:669–80.
70. Johnson JO, Pioro EP, Boehringer A, Chia R, Feit H, Renton AE, et al. Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat Neurosci. 2014;17:664–6. Johnson et al were the first to link matrin-3 and ALS through the identification of mutations in fALS and sALS cases and the observations of matrin-3 proteins in aggregates of ALS patients.
71. Lin K-P, Tsai P-C, Liao Y-C, Chen W-T, Tsai C-P, Soong B-W, et al. Mutational analysis of MATR3 in Taiwanese patients with amyotrophic lateral sclerosis. Neurobiol Aging. 2005;2015(36):e1–4.
72. Origone P, Verdiani S, Bandettini Di Poggio M, Zuccarino R, Vignolo M, Caponnetto C, et al. A novel Arg147Trp MATR3 missense mutation in a slowly progressive ALS Italian patient. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration. 2015; 1–2.
73. Leblond CS, Gan-Or Z, Spiegelman D, Laurent SB, Szuto A, Hodgkinson A. , 2016, Replication study of MATR3 in familial and sporadic amyotrophic lateral sclerosis, Neurobiology of Aging, 37, 209.e17–209.21.
74. Millecamps S, de Septenville A, Teyssou E, Daniau M, Camuzat A, Albert M, et al. Genetic analysis of matrin 3 gene in French amyotrophic lateral sclerosis patients and frontotemporal lobar degeneration with amyotrophic lateral sclerosis patients. Neurobiol Aging. 2014;35:2882.e13–5.
75. Fifita JA, Williams KL, Mccann EP, O'Brien A, Bauer DC, Nicholson GA, et al. Mutation analysis of MATR3 in Australian familial amyotrophic lateral sclerosis. Neurobiol Aging. 2015;1602(36):e1–2.
76. Ling S-C, Albuquerque CP, Han JS, Lagier-Tourenne C, Tokunaga S, Zhou H, et al. ALS-associated mutations in TDP-43 increase its stability and promote TDP-43 complexes with FUS/TLS. Proc Natl Acad Sci. 2010;107:13318–23.
77. Salton M, Elkon R, Borodina T, Davydov A, Yaspo M-L, Halperin E, et al. Matrin 3 binds and stabilizes mRNA. PLoS One. 2011;6:e23882.
78. Jones AR, Troakes C, King A, Sahni V, De Jong S, Bossers K, et al. Stratified gene expression analysis identifies major amyotrophic lateral sclerosis genes. Neurobiol Aging. 2006;2015(36):e1–9.
79. 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;347:1436–41. Cirulli et al. reported a large collaborative exome sequencing effort using >3,000 ALS cases. Several variations in known ALS genes were replicated and TBK1 mutations leading to loss of function were first identified for the first time.
80. Freischmidt A, Wieland T, Richter B, Ruf W, Schaeffer V, Müller K, et al. Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat Neurosci. 2015;18:631–6.
81. 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;130:77–92.
82. Williams KL, Mccann EP, Fifita JA, Zhang K, Duncan EL, Leo PJ, et al. Novel TBK1 truncating mutation in a familial amyotrophic lateral sclerosis patient of Chinese origin. Neurobiol Aging. 2015;36:3334.e1–5.
83. Kenna KP, McLaughlin RL, Byrne S, Elamin M, Heverin M, Kenny EM, et al. Delineating the genetic heterogeneity of ALS using targeted high-throughput sequencing. J Med Genet. 2013;50:776–83.
84. van Blitterswijk M, van Es MA, Hennekam EAM, Dooijes D, van Rheenen W, Medic J, et al. Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Hum Mol Genet. 2012;21:3776–84.
85. Al-Chalabi A, Hardiman O. The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol. 2013;9:617–28.
86. Veltman JA, Brunner HG. De novo mutations in human genetic disease. Nat Rev Genet. 2012;13:565–75.
87. Alexander MD, Traynor BJ, Miller N, Corr B, Frost E, McQuaid S, et al. “True” sporadic ALS associated with a novel SOD-1 mutation. Ann Neurol. 2002;52:680–3.
88. DeJesus-Hernandez M, Kocerha J, Finch N, Crook R, Baker M, Desaro P, et al. De novo truncating FUS gene mutation as a cause of sporadic amyotrophic lateral sclerosis. Hum Mutat. 2010;31:E1377–89.
89. Chiò A, Calvo A, Moglia C, Ossola I, Brunetti M, Sbaiz L, et al. A de novo missense mutation of the FUS gene in a “true” sporadic ALS case. Neurobiol Aging. 2011;32:553.e23–6.
90. Calvo A, Moglia C, Canosa A, Brunetti M, Barberis M, Traynor BJ, et al. A de novo nonsense mutation of the FUS gene in an apparently familial amyotrophic lateral sclerosis case. Neurobiol Aging. 2014;35:1513.e7–11.
91. Hübers A, Just W, Rosenbohm A, Müller K, Marroquin N, Goebel I, et al. De novo FUS mutations are the most frequent genetic cause in early-onset German ALS patients. Neurobiol Aging. 2015;36:3117.e1–3117.e6. Hübers et al. identified de novo mutations in FUS as the most important cause of early-onset ALS. This was one of the first attempt to identify de novo mutations in a large cohort of ALS cases.
92. Laffita-Mesa JM, Rodríguez Pupo JM, Moreno Sera R, Vázquez Mojena Y, Kourí V, Laguna-Salvia L, et al. De novo mutations in ataxin-2 gene and ALS risk. PLoS One. 2013;8:e70560.
93. Elden AC, Kim H-J, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X, et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010;466:1069–75.
94. Chesi A, Staahl BT, Jovičić A, Couthouis J, Fasolino M, Raphael AR, et al. Exome sequencing to identify de novo mutations in sporadic ALS trios. Nat Neurosci. 2013;16:851–5. Chesi et al. reported the first large study aime de novo mutation in ALS cases identifying mutations in chromatin regulator genes.
95. Steinberg KM, Yu B, Koboldt DC, Mardis ER, Pamphlett R. Exome sequencing of case-unaffected-parents trios reveals recessive and de novo genetic variants in sporadic ALS. Sci Rep. 2015;5:9124.
96. López Castel A, Cleary JD, Pearson CE. Repeat instability as the basis for human diseases and as a potential target for therapy. Nat Rev Mol Cell Biol. 2010;11:165–70.
97. Nordin A, Akimoto C, Wuolikainen A, Alstermark H, Jonsson P, Birve A, et al. Extensive size variability of the GGGGCC expansion in C9orf72 in both neuronal and non-neuronal tissues in 18 patients with ALS or FTD. Hum Mol Genet. 2015;24:3133–42.
98. Harms MB, Cady J, Zaidman C, Cooper P, Bali T, Allred P, et al. Lack of C9ORF72 coding mutations supports a gain of function for repeat expansions in amyotrophic lateral sclerosis. Neurobiol Aging. 2013;34:2234.e13–9.
99. Leblond CS, Kaneb HM, Dion PA, Rouleau GA. Dissection of genetic factors associated with amyotrophic lateral sclerosis. Exp Neurol. 2014;262 Pt B:91–101.
100. Daoud H, Suhail H, Sabbagh M, Belzil V, Szuto A, Dionne-Laporte A, et al. C9orf72 hexanucleotide repeat expansions as the causative mutation for chromosome 9p21-linked amyotrophic lateral sclerosis and frontotemporal dementia. Arch Neurol. 2012;69:1159–63.
101. van Es MA, Veldink JH, Saris CGJ, Blauw HM, van Vught PWJ, Birve A, et al. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat. Genet. 2009;41:1083–7.