Abstract
We present two cases of patients with juvenile amyotrophic lateral sclerosis (ALS), who had no history of familial ALS. The symptoms of both patients started as weakness of the unilateral upper limb and neck, and extended to bulbar and respiratory weakness in a relatively short period. Of note, the first patient was mentally retarded before the onset of weakness. Fused in sarcoma/translocated in liposarcoma (FUS/TLS) gene analyses revealed mutations of p. G492EfsX527 (c. 1475delG), which is a novel deletion/frameshift mutation, in the first patient and p. R514S mutation (c. 1542G > T) in the second patient. Molecular analysis revealed that the mutant FUS/TLS, especially the deletion/frameshift mutation, showed significant cytoplasmic localization in transfected motor neuron-like cells. Our findings suggest the association of mental retardation with the FUS/TLS mutation. Further investigation, including the effect of FUS/TLS on cognitive function, would aid better understanding of FUS/TLS proteinopathies.
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References
Kiernan MC, Vucic S, Cheah BC et al (2011) Amyotrophic lateral sclerosis. Lancet 377:942–955
Neumann M, Sampathu DM, Kwong LK et al (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133
Arai T, Hasegawa M, Akiyama H et al (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611
Deng HX, Zhai H, Bigio EH et al (2010) FUS-immunoreactive inclusions are a common feature in sporadic and non-SOD1 familial amyotrophic lateral sclerosis. Ann Neurol 67:739–748
Kwiatkowski TJ Jr, Bosco DA, Leclerc AL et al (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208
Vance C, Rogelj B, Hortobagyi T et al (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211
Neumann M, Roeber S, Kretzschmar HA et al (2009) Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol 118:605–616
Neumann M, Rademakers R, Roeber S et al (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132:2922–2931
Munoz DG, Neumann M, Kusaka H et al (2009) FUS pathology in basophilic inclusion body disease. Acta Neuropathol 118:617–627
Yan J, Deng HX, Siddique N et al (2010) Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia. Neurology 75:807–814
Mackenzie IR, Ansorge O, Strong M et al (2011) Pathological heterogeneity in amyotrophic lateral sclerosis with FUS mutations: two distinct patterns correlating with disease severity and mutation. Acta Neuropathol 122:87–98
Josephs KA, Whitwell JL, Parisi JE et al (2010) Caudate atrophy on MRI is a characteristic feature of FTLD-FUS. Eur J Neurol 17:969–975
Baumer D, Hilton D, Paine SM et al (2010) Juvenile ALS with basophilic inclusions is a FUS proteinopathy with FUS mutations. Neurology 75:611–618
Nelson JS, Prensky AL (1972) Sporadic juvenile amyotrophic lateral sclerosis. A clinicopathological study of a case with neuronal cytoplasmic inclusions containing RNA. Arch Neurol 27:300–306
Lee BJ, Cansizoglu AE, Suel KE et al (2006) Rules for nuclear localization sequence recognition by karyopherin beta 2. Cell 126:543–558
Dormann D, Rodde R, Edbauer D et al (2010) ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J 29:2841–2857
Ito D, Seki M, Tsunoda Y, Uchiyama H, Suzuki N (2011) Nuclear transport impairment of amyotrophic lateral sclerosis-linked mutations in FUS/TLS. Ann Neurol 69:152–162
Kino Y, Washizu C, Aquilanti E et al (2011) Intracellular localization and splicing regulation of FUS/TLS are variably affected by amyotrophic lateral sclerosis-linked mutations. Nucleic Acids Res 39:2781–2798
Dormann D, Haass C (2011) TDP-43 and FUS: a nuclear affair. Trends Neurosci 34:339–348
Yamashita S, Mori A, Kimura E et al (2010) DJ-1 forms complexes with mutant SOD1 and ameliorates its toxicity. J Neurochem 113:860–870
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We would like to thank Drs. Ohyagi and Fukunaga (Kyushu University, Department of Neurology) for providing NSC-34 cells.
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The authors declare that there are no conflicts of interest. The authors are fully responsible for the content and writing of the paper.
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S. Yamashita, A. Mori and H. Sakaguchi contributed equally to this work.
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Yamashita, S., Mori, A., Sakaguchi, H. et al. Sporadic juvenile amyotrophic lateral sclerosis caused by mutant FUS/TLS: possible association of mental retardation with this mutation. J Neurol 259, 1039–1044 (2012). https://doi.org/10.1007/s00415-011-6292-6
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DOI: https://doi.org/10.1007/s00415-011-6292-6