Genotype-phenotype relationship in hereditary amyotrophic lateral sclerosis

Translational Neurodegeneration

Yukio Ando¹  Satoshi Yamashita¹ 

[1] Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan

关键词: Familial ALS (FALS);    Sporadic ALS (SALS);    Phenotype;    Genotype;    Amyotrophic lateral sclerosis (ALS);   

Others  :  1220775
DOI  :  10.1186/s40035-015-0036-y

 received in 2015-04-15, accepted in 2015-07-17,  发布年份 2015

【 摘 要 】

Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. It is characterized by neuronal loss and degeneration of the upper motor neurons (UMNs) and lower motor neurons (LMNs), and is usually fatal due to respiratory failure within 3–5 years of onset. Although approximately 5–10 % of patients with ALS have an inherited form of the disease, the distinction between hereditary and apparently sporadic ALS (SALS) seems to be artificial. Thus, genetic factors play a role in all types of ALS, to a greater or lesser extent. During the decade of upheaval, the evolution of molecular genetics technology has rapidly advanced our genetic knowledge about the causes of ALS, and the relationship between the genetic subtypes and clinical phenotype. In this review, we will focus on the possible genotype-phenotype correlation in hereditary ALS. Uncovering the identity of the genetic factors in ALS will not only improve the accuracy of ALS diagnosis, but may also provide new approaches for preventing and treating the disease.

【 授权许可】

   
2015 Yamashita and Ando.

【 图 表 】

Fig. 1.

Fig. 2.

Fig. 3.

Fig. 4.

【 参考文献 】

• [1]Siddique T, Figlewicz DA, Pericak-Vance MA, Haines JL, Rouleau G, Jeffers AJ, et al.: Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity. N Engl J Med. 1991, 324:1381-4.
• [2]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.
• [3]Cudkowicz ME, McKenna-Yasek D, Sapp PE, Chin W, Geller B, Hayden DL, et al.: Epidemiology of mutations in superoxide dismutase in amyotrophic lateral sclerosis. Ann Neurol. 1997, 41:210-21.
• [4]Regal L, Vanopdenbosch L, Tilkin P, Van den Bosch L, Thijs V, Sciot R et al. The G93C mutation in superoxide dismutase 1: clinicopathologic phenotype and prognosis. Arch Neurol. 2006;63: 262-7. doi:10.1001/archneur.63.2.262
• [5]Aoki M, Warita H, Itoyama Y: Amyotrophic lateral sclerosis with the SOD1 mutations. Rinsho Shinkeigaku 2008, 48:966-9.
• [6]Yamashita S, Kimura E, Yamamoto F, Migita A, Kanda E, Mita S et al. Flexor-dominant myopathic phenotype in patients with His46Arg substitution in the Cu/Zn superoxide dismutase gene. J Neurol Sci. 2009;281: 6-10. doi:10.1016/j.jns.2009.03.010
• [7]Crugnola V, Lamperti C, Lucchini V, Ronchi D, Peverelli L, Prelle A et al. Mitochondrial respiratory chain dysfunction in muscle from patients with amyotrophic lateral sclerosis. Arch Neurol. 2010;67: 849-54. doi:10.1001/archneurol.2010.128
• [8]Hadano S, Hand CK, Osuga H, Yanagisawa Y, Otomo A, Devon RS, et al.: A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet. 2001, 29:166-73.
• [9]Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, et al.: The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet. 2001, 29:160-5.
• [10]Siddiqi S, Foo JN, Vu A, Azim S, Silver DL, Mansoor A, et al.: A novel splice-site mutation in ALS2 establishes the diagnosis of juvenile amyotrophic lateral sclerosis in a family with early onset anarthria and generalized dystonias. PLoS One. 2014., 9Article ID e113258
• [11]Moreira MC, Klur S, Watanabe M, Nemeth AH, Le Ber I, Moniz JC, et al.: Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nat Genet. 2004, 36:225-7.
• [12]Chen YZ, 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.
• [13]De Jonghe P, Auer-Grumbach M, Irobi J, Wagner K, Plecko B, Kennerson M, et al.: Autosomal dominant juvenile amyotrophic lateral sclerosis and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for the same disorder? Brain. 2002, 125:1320-5.
• [14]Saracchi E, Castelli M, Bassi MT, Brighina E, Cereda D, Marzorati L, et al.: A novel heterozygous SETX mutation in a patient presenting with chorea and motor neuron disease. Amyotroph Lateral Scler Frontotemporal Degener. 2014, 15:138-40.
• [15]Arning L, Epplen JT, Rahikkala E, Hendrich C, Ludolph AC, Sperfeld AD: The SETX missense variation spectrum as evaluated in patients with ALS4-like motor neuron diseases. Neurogenetics. 2013, 14:53-61.
• [16]Stevanin G, Santorelli FM, Azzedine H, Coutinho P, Chomilier J, Denora PS et al. Mutations in SPG11, encoding spatacsin, are a major cause of spastic paraplegia with thin corpus callosum. Nat Genet. 2007;39: 366-72. doi:10.1038/ng1980
• [17]Orlacchio A, Babalini C, Borreca A, Patrono C, Massa R, Basaran S et al. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain. 2010;133: 591-8. doi:10.1093/brain/awp325
• [18]Daoud H, Zhou S, Noreau A, Sabbagh M, Belzil V, Dionne-Laporte A et al. Exome sequencing reveals SPG11 mutations causing juvenile ALS. Neurobiol Aging. 2012;33: 839 e5-9. doi:10.1016/j.neurobiolaging.2011.11.012
• [19]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: 1205-8. doi:10.1126/science.1166066
• [20]Vance C, Rogelj B, Hortobagyi 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. doi:10.1126/science.1165942
• [21]Suzuki N, Aoki M, Warita H, Kato M, Mizuno H, Shimakura N, et al.: FALS with FUS mutation in Japan, with early onset, rapid progress and basophilic inclusion. J Hum Genet. 2010, 55:252-4.
• [22]Yamashita S, Mori A, Sakaguchi H, Suga T, Ishihara D, Ueda A, et al.: Sporadic juvenile amyotrophic lateral sclerosis caused by mutant FUS/TLS: possible association of mental retardation with this mutation. J Neurol. 2012, 259:1039-44.
• [23]Munoz DG. FUS mutations in sporadic juvenile ALS: another step toward understanding ALS pathogenesis. Neurology. 2010;75: 584-5. doi:10.1212/WNL.0b013e3181ed9ee4
• [24]Baumer D, Hilton D, Paine SM, Turner MR, Lowe J, Talbot K et al. Juvenile ALS with basophilic inclusions is a FUS proteinopathy with FUS mutations. Neurology. 2010;75: 611-8. doi:10.1212/WNL.0b013e3181ed9cde
• [25]Conte A, Lattante S, Zollino M, Marangi G, Luigetti M, Del Grande A et al. P525L FUS mutation is consistently associated with a severe form of juvenile amyotrophic lateral sclerosis. Neuromuscul Disord. 2012;22: 73-5. doi:10.1016/j.nmd.2011.08.003
• [26]Blair IP, Williams KL, Warraich ST, Durnall JC, Thoeng AD, Manavis J, et al.: FUS mutations in amyotrophic lateral sclerosis: clinical, pathological, neurophysiological and genetic analysis. J Neurol Neurosurg Psychiatry. 2010, 81:639-45.
• [27]Yan J, Deng HX, Siddique N, Fecto F, Chen W, Yang Y et al. Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia. Neurology. 2010;75: 807-14. doi:10.1212/WNL.0b013e3181f07e0c
• [28]Dormann D, Madl T, Valori CF, Bentmann E, Tahirovic S, Abou-Ajram C et al. Arginine methylation next to the PY-NLS modulates Transportin binding and nuclear import of FUS. EMBO J. 2012;31: 4258-75. doi:10.1038/emboj.2012.261
• [29]Dormann D, Rodde R, Edbauer D, Bentmann E, Fischer I, Hruscha A et al. ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J. 2010;29: 2841-57. doi:10.1038/emboj.2010.143
• [30]Kino Y, Washizu C, Aquilanti E, Okuno M, Kurosawa M, Yamada M et al. Intracellular localization and splicing regulation of FUS/TLS are variably affected by amyotrophic lateral sclerosis-linked mutations. Nucleic Acids Res. 2011;39: 2781-98. doi:10.1093/nar/gkq1162
• [31]Waibel S, Neumann M, Rabe M, Meyer T, Ludolph AC. Novel missense and truncating mutations in FUS/TLS in familial ALS. Neurology. 2010;75: 815-7. doi:10.1212/WNL.0b013e3181f07e26
• [32]Nishimura AL, Mitne-Neto M, Silva HC, Richieri-Costa A, Middleton S, Cascio D, et al.: A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am J Hum Genet. 2004, 75:822-31.
• [33]Marques VD, Barreira AA, Davis MB, Abou-Sleiman PM, Silva WA Jr, Zago MA, et al.: Expanding the phenotypes of the Pro56Ser VAPB mutation: proximal SMA with dysautonomia. Muscle Nerve. 2006, 34:731-9.
• [34]Greenway MJ, Andersen PM, Russ C, Ennis S, Cashman S, Donaghy C et al. ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nat Genet. 2006;38: 411-3. doi:10.1038/ng1742
• [35]van Es MA, Diekstra FP, Veldink JH, Baas F, Bourque PR, Schelhaas HJ et al. A case of ALS-FTD in a large FALS pedigree with a K17I ANG mutation. Neurology. 2009;72: 287-8. doi:10.1212/01.wnl.0000339487.84908.00
• [36]van Es MA, Schelhaas HJ, van Vught PW, Ticozzi N, Andersen PM, Groen EJ, et al.: Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis. Ann Neurol. 2011, 70:964-73.
• [37]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. doi:10.1126/science.1154584
• [38]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. doi:10.1038/ng.132
• [39]Van Deerlin VM, Leverenz JB, Bekris LM, Bird TD, Yuan W, Elman LB et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 2008;7: 409-16. doi:10.1016/S1474-4422(08)70071-1
• [40]Yokoseki A, Shiga A, Tan CF, Tagawa A, Kaneko H, Koyama A, et al.: TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol. 2008, 63:538-42.
• [41]Corcia P, Valdmanis P, Millecamps S, Lionnet C, Blasco H, Mouzat K et al. Phenotype and genotype analysis in amyotrophic lateral sclerosis with TARDBP gene mutations. Neurology. 2012;78: 1519-26. doi:10.1212/WNL.0b013e3182553c88
• [42]Chow CY, Zhang Y, Dowling JJ, Jin N, Adamska M, Shiga K et al. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature. 2007;448: 68-72. doi:10.1038/nature05876
• [43]Chow CY, Landers JE, Bergren SK, Sapp PC, Grant AE, Jones JM et al. Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS. Am J Hum Genet. 2009;84: 85-8. doi:10.1016/j.ajhg.2008.12.010
• [44]Maruyama H, Morino H, Ito H, Izumi Y, Kato H, Watanabe Y et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature. 2010;465: 223-6. doi:10.1038/nature08971
• [45]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.
• [46]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, 18:631-6.
• [47]Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, Lopes-Cendes I, et al.: Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet. 1996, 14:269-76.
• [48]Elden AC, Kim HJ, 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. doi:10.1038/nature09320
• [49]Chen Y, Huang R, Yang Y, Chen K, Song W, Pan P et al. Ataxin-2 intermediate-length polyglutamine: a possible risk factor for Chinese patients with amyotrophic lateral sclerosis. Neurobiol Aging. 2011;32: 1925 e1-5. doi:10.1016/j.neurobiolaging.2011.05.015
• [50]Liu X, Lu M, Tang L, Zhang N, Chui D, Fan D. ATXN2 CAG repeat expansions increase the risk for Chinese patients with amyotrophic lateral sclerosis. Neurobiol Aging. 2013;34: 2236 e5-8. doi:10.1016/j.neurobiolaging.2013.04.009
• [51]Van Damme P, Veldink JH, van Blitterswijk M, Corveleyn A, van Vught PW, Thijs V et al. Expanded ATXN2 CAG repeat size in ALS identifies genetic overlap between ALS and SCA2. Neurology. 2011;76: 2066-72. doi:10.1212/WNL.0b013e31821f445b
• [52]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: 857-64. doi:10.1016/j.neuron.2010.11.036
• [53]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, 36:377-81.
• [54]Gonzalez-Perez P, Cirulli ET, Drory VE, Dabby R, Nisipeanu P, Carasso RL et al. Novel mutation in VCP gene causes atypical amyotrophic lateral sclerosis. Neurology. 2012;79: 2201-8. doi:10.1212/WNL.0b013e318275963b
• [55]Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature. 2011;477: 211-5. doi:10.1038/nature10353
• [56]Al-Saif A, Al-Mohanna F, Bohlega S: A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Ann Neurol. 2011, 70:913-9.
• [57]Fecto F, Siddique T: SIGMAR1 mutations, genetic heterogeneity at the chromosome 9p locus, and the expanding etiological diversity of amyotrophic lateral sclerosis. Ann Neurol. 2011, 70:867-70.
• [58]Belzil VV, Daoud H, Camu W, Strong MJ, Dion PA, Rouleau GA. Genetic analysis of SIGMAR1 as a cause of familial ALS with dementia. Eur J Hum Genet. 2013;21: 237-9. doi:10.1038/ejhg.2012.135
• [59]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, 37:806-8.
• [60]Parkinson N, Ince PG, Smith MO, Highley R, Skibinski G, Andersen PM et al. ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B). Neurology. 2006;67: 1074-7. doi:10.1212/01.wnl.0000231510.89311.8b
• [61]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., 5Article ID e9872
• [62]Wu CH, Fallini C, Ticozzi N, Keagle PJ, Sapp PC, Piotrowska K et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature. 2012;488: 499-503. doi:10.1038/nature11280
• [63]Takahashi Y, Fukuda Y, Yoshimura J, Toyoda A, Kurppa K, Moritoyo H, et al.: ERBB4 mutations that disrupt the neuregulin-ErbB4 pathway cause amyotrophic lateral sclerosis type 19. Am J Hum Genet. 2013, 93:900-5.
• [64]Kim HJ, Kim NC, Wang YD, 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.
• [65]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.
• [66]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.
• [67]Yamashita S, Mori A, Nishida Y, Kurisaki R, Tawara N, Nishikami T, et al.: Clinicopathological features of the first Asian family having vocal cord and pharyngeal weakness with distal myopathy due to a MATR3 mutation. Neuropathol Appl Neurobiol. 2015, 41:391-8.
• [68]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. doi:10.1016/j.neuron.2011.09.011
• [69]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: 257-68. doi:10.1016/j.neuron.2011.09.010
• [70]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: 323-30. doi:10.1016/S1474-4422(12)70043-1.
• [71]Rutherford NJ, Heckman MG, Dejesus-Hernandez M, Baker MC, Soto-Ortolaza AI, Rayaprolu S et al. Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype. Neurobiol Aging. 2012;33: 2950 e5-7. doi:10.1016/j.neurobiolaging.2012.07.005
• [72]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.
• [73]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.
• [74]Fanos JH, Gelinas DF, Miller RG: "You have shown me my end": attitudes toward presymptomatic testing for familial amyotrophic lateral sclerosis. Am J Med Genet A. 2004, 129A:248-53.