neurogenetics

, Volume 14, Issue 1, pp 53–61 | Cite as

The SETX missense variation spectrum as evaluated in patients with ALS4-like motor neuron diseases

  • Larissa Arning
  • Jörg T. Epplen
  • Elisa Rahikkala
  • Corinna Hendrich
  • Albert C. Ludolph
  • Anne-Dorte Sperfeld
Short Communication

Abstract

Mutations in the senataxin (SETX) gene can cause amyotrophic lateral sclerosis 4 (ALS4), an autosomal dominant form of juvenile onset amyotrophic lateral sclerosis, or result in autosomal recessive ataxia with oculomotor apraxia type 2. Great caution regarding the possible disease causation, especially of missense variations, has to be taken. Here, we evaluated the significance of all previously reported SETX missense mutations as well as six newly identified variations in 54 patients suspected of having ALS4. Yet, epidemiologic and in silico evidence indicates that all newly identified variations and two previously published ALS4-related missense variations (C1554G and I2547T) are most likely non-pathogenic, demonstrating the problems of interpretation of SETX missense alleles in the absence of functional assays.

Keywords

SETX·amyotrophic lateral sclerosis ALS4 Ataxia AOA2 Missense mutations 

Notes

Acknowledgments

This work was supported by a grant from the Deutsche Gesellschaft für Muskelkranke e.V. (DGM).

References

  1. 1.
    De Jonghe P, Auer-Grumbach M, Irobi J, Wagner K, Plecko B, Kennerson M, Zhu D, De Vriendt E, Van Gerwen V, Nicholson G, Hartung HP, Timmerman V (2002) Autosomal dominant juvenile amyotrophic lateral sclerosis and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for the same disorder? Brain 125(Pt 6):1320–1325PubMedCrossRefGoogle Scholar
  2. 2.
    Moreira MC, Klur S, Watanabe M, Németh AH, Le Ber I, Moniz JC, Tranchant C, Aubourg P, Tazir M, Schöls L, Pandolfo M, Schulz JB, Pouget J, Calvas P, Shizuka-Ikeda M, Shoji M, Tanaka M, Izatt L, Shaw CE, M'Zahem A, Dunne E, Bomont P, Benhassine T, Bouslam N, Stevanin G, Brice A, Guimarães J, Mendonça P, Barbot C, Coutinho P, Sequeiros J, Dürr A, Warter JM, Koenig M (2004) Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nat Genet 36(3):225–227PubMedCrossRefGoogle Scholar
  3. 3.
    Chance PF, Rabin BA, Ryan SG, Ding Y, Scavina M, Crain B, Griffin JW, Cornblath DR (1998) Linkage of the gene for an autosomal dominant form of juvenile amyotrophic lateral sclerosis to chromosome 9q34. Am J Hum Genet 62(3):633–640PubMedCrossRefGoogle Scholar
  4. 4.
    Rabin BA, Griffin JW, Crain BJ, Scavina M, Chance PF, Cornblath DR (1999) Autosomal dominant juvenile amyotrophic lateral sclerosis. Brain 122(Pt 8):1539–1550PubMedCrossRefGoogle Scholar
  5. 5.
    Blair IP, Bennett CL, Abel A, Rabin BA, Griffin JW, Fischbeck KH, Cornblath DR, Chance PF (2000) A gene for autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4) localizes to a 500-kb interval on chromosome 9q34. Neurogenetics 3(1):1PubMedGoogle Scholar
  6. 6.
    Chen YZ, Bennett CL, Huynh HM, Blair IP, Puls I, Irobi J, Dierick I, Abel A, Kennerson ML, Rabin BA, Nicholson GA, Auer-Grumbach M, Wagner K, De Jonghe P, Griffin JW, Fischbeck KH, Timmerman V, Cornblath DR, Chance PF (2004) DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet 74(6):1128–1135PubMedCrossRefGoogle Scholar
  7. 7.
    Avemaria F, Lunetta C, Tarlarini C, Mosca L, Maestri E, Marocchi A, Melazzini M, Penco S, Corbo M (2011) Mutation in the senataxin gene found in a patient affected by familial ALS with juvenile onset and slow progression. Amyotroph Lateral Scler 12(3):228–230PubMedCrossRefGoogle Scholar
  8. 8.
    Rudnik-Schöneborn S, Arning L, Epplen JT, Zerres K (2011) SETX gene mutation in a family diagnosed autosomal dominant proximal spinal muscular atrophy. Neuromuscul Disord 22(3):258–262PubMedCrossRefGoogle Scholar
  9. 9.
    Zhao ZH, Chen WZ, Wu ZY, Wang N, Zhao GX, Chen WJ, Murong SX (2011) A novel mutation in the senataxin gene identified in a Chinese patient with sporadic amyotrophic lateral sclerosis. Amyotroph Lateral Scler 10(2):118–122CrossRefGoogle Scholar
  10. 10.
    Hirano M, Quinzii CM, Mitsumoto H, Hays AP, Roberts JK, Richard P, Rowland LP (2011) Senataxin mutations and amyotrophic lateral sclerosis. Amyotroph Lateral Scler 12(3):223–227PubMedCrossRefGoogle Scholar
  11. 11.
    Brooks BR, Miller RG, Swash M, Munsat TL, World Federation of Neurology Research Group on Motor Neuron Diseases (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis (2000). Amyotroph Lateral Scler Other Motor Neuron Disord 201(5):293–299CrossRefGoogle Scholar
  12. 12.
    Ng PC, Henikoff S (2001) Predicting deleterious amino acid substitutions. Genome Res 11(5):863–874PubMedCrossRefGoogle Scholar
  13. 13.
    Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7(4):248–249PubMedCrossRefGoogle Scholar
  14. 14.
    Li B, Krishnan VG, Mort ME, Xin F, Kamati KK, Cooper DN, Mooney SD, Radivojac P (2009) Automated inference of molecular mechanisms of disease from amino acid substitutions. Bioinformatics 25(21):2744–2750PubMedCrossRefGoogle Scholar
  15. 15.
    Fogel BL, Perlman S (2006) Novel mutations in the senataxin DNA/RNA helicase domain in ataxia with oculomotor apraxia 2. Neurology 67(11):2083–2084PubMedCrossRefGoogle Scholar
  16. 16.
    Bernard V, Stricker S, Kreuz F, Minnerop M, Gillessen-Kaesbach G, Zühlke C (2008) Ataxia with oculomotor apraxia type 2: novel mutations in six patients with juvenile age of onset and elevated serum alpha-fetoprotein. Neuropediatrics 39(6):347–350PubMedCrossRefGoogle Scholar
  17. 17.
    Asaka T, Yokoji H, Ito J, Yamaguchi K, Matsushima A (2006) Autosomal recessive ataxia with peripheral neuropathy and elevated AFP: novel mutations in SETX. Neurology 66(10):1580–1581PubMedCrossRefGoogle Scholar
  18. 18.
    Bassuk AG, Chen YZ, Batish SD, Nagan N, Opal P, Chance PF, Bennett CL (2007) In cis autosomal dominant mutation of Senataxin associated with tremor/ataxia syndrome. Neurogenetics 8(1):45–49PubMedCrossRefGoogle Scholar
  19. 19.
    Duquette A, Roddier K, McNabb-Baltar J, Gosselin I, St-Denis A, Dicaire MJ, Loisel L, Labuda D, Marchand L, Mathieu J, Bouchard JP, Brais B (2005) Mutations in senataxin responsible for Quebec cluster of ataxia with neuropathy. Ann Neurol 57(3):408–414PubMedCrossRefGoogle Scholar
  20. 20.
    Criscuolo C, Chessa L, Di Giandomenico S, Mancini P, Saccà F, Grieco GS, Piane M, Barbieri F, De Michele G, Banfi S, Pierelli F, Rizzuto N, Santorelli FM, Gallosti L, Filla A, Casali C (2006) Ataxia with oculomotor apraxia type 2: a clinical, pathologic, and genetic study. Neurology 66(8):1207–1210PubMedCrossRefGoogle Scholar
  21. 21.
    Anheim M, Monga B, Fleury M, Charles P, Barbot C, Salih M, Delaunoy JP, Fritsch M, Arning L, Synofzik M, Schöls L, Sequeiros J, Goizet C, Marelli C, Le Ber I, Koht J, Gazulla J, De Bleecker J, Mukhtar M, Drouot N, Ali-Pacha L, Benhassine T, Chbicheb M, M'Zahem A, Hamri A, Chabrol B, Pouget J, Murphy R, Watanabe M, Coutinho P, Tazir M, Durr A, Brice A, Tranchant C, Koenig M (2009) Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients. Brain 132(Pt 10):2688–2698PubMedCrossRefGoogle Scholar
  22. 22.
    Chen YZ, Hashemi SH, Anderson SK, Huang Y, Moreira MC, Lynch DR, Glass IA, Chance PF, Bennett CL (2006) Senataxin, the yeast Sen1p orthologue: characterization of a unique protein in which recessive mutations cause ataxia and dominant mutations cause motor neuron disease. Neurobiol Dis 23(1):97–108PubMedCrossRefGoogle Scholar
  23. 23.
    Anheim M, Fleury MC, Franques J, Moreira MC, Delaunoy JP, Stoppa-Lyonnet D, Koenig M, Tranchant C (2008) Clinical and molecular findings of ataxia with oculomotor apraxia type 2 in 4 families. Arch Neurol 65(7):958–962PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Larissa Arning
    • 1
  • Jörg T. Epplen
    • 1
  • Elisa Rahikkala
    • 2
  • Corinna Hendrich
    • 3
    • 5
  • Albert C. Ludolph
    • 3
  • Anne-Dorte Sperfeld
    • 3
    • 4
  1. 1.Department of Human GeneticsRuhr UniversityBochumGermany
  2. 2.Department of Clinical Genetics, Oulu University HospitalUniversity of OuluOuluFinland
  3. 3.Department of NeurologyUniversity of UlmUlmGermany
  4. 4.Neurologische KlinikIbbenbürenGermany
  5. 5.Neurologische KlinikKemptenGermany

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