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ATXN-2 CAG repeat expansions are interrupted in ALS patients

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Abstract

It has recently been suggested that short expansions of CAG repeat in the gene ATXN-2 causing SCA2 (spinocerebellar ataxia type 2) are associated with an increased risk of amyotrophic lateral sclerosis (ALS) in the populations of the USA and northern Europe. In this study, we investigated the role of ATXN-2 in Italian patients clinically diagnosed with ALS and characterized the molecular structure of ATXN-2 expansions. We assessed the size of the CAG repeat in ATXN-2 exon 1 in 232 Italian ALS patients and 395 matched controls. ATXN-2 expanded alleles containing >30 repeats have been observed in seven sporadic ALS patients (3.0%), while being absent in the controls (p = 0.00089). Four out of the seven patients had an ATXN-2 allele in the intermediate-fully pathological range: one with 32 repeats, 2 with 33 repeats and 1 with 37 repeats, accounting for 1.7% of the ALS cohort. Sequencing of expanded (>32) alleles showed that they were all interrupted with at least one CAA triplet. ATXN-2 alleles with the same length and structure have been reported in SCA2 patients with parkinsonism or in familial and sporadic Parkinson. Conversely, the phenotype of the present patients was typically ALS with no signs or symptoms of ataxia or parkinsonism. In conclusion, the findings of ATXN-2 expansions in pure ALS cases suggest that ALS may be a third phenotype (alongside ataxia/parkinsonism and pure Parkinson) associated with ATXN-2 interrupted alleles.

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References

  • 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. Amyotroph Lateral Scler Other Motor Neuron Disord 1:293–299

    Google Scholar 

  • Byrne S, Walsh C, Lynch C, Bede P, Elamin M, Kenna K, McLaughlin R, Hardiman O (2010) Rate of familial amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. doi:10.1136/jnnp.2010.224501

  • Cancel G, Dürr A, Didierjean O, Imbert G, Bürk K, Lezin A, Belal S, Benomar A, Abada-Bendib M, Vial C, Guimarães J, Chneiweiss H, Stevanin G, Yvert G, Abbas N, Saudou F, Lebre AS, Yahyaoui M, Hentati F, Vernant JC, Klockgether T, Mandel JL, Agid Y, Brice A (1997) Molecular and clinical correlations in spinocerebellar ataxia 2: a study of 32 families. Hum Mol Genet 6:709–715

    Article  PubMed  CAS  Google Scholar 

  • Charles P, Camuzat A, Benammar N, Sellal F, Destée A, Bonnet AM, Lesage S, Le Ber I, Stevanin G, Dürr A, Brice A et al (2007) French Parkinson’s Disease Genetic Study Group. Are interrupted SCA2 CAG repeat expansions responsible for parkinsonism? Neurology 69:1970–1975

    Article  PubMed  CAS  Google Scholar 

  • Costanzi-Porrini S, Tessarolo D, Abbruzzese C, Liguori M, Ashizawa T, Giacanelli M (2000) An interrupted 34-CAG repeat SCA-2 allele in patients with sporadic spinocerebellar ataxia. Neurology 54:491–493

    Google Scholar 

  • Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X, Armakola M, Geser F, Greene R, Lu MM, Padmanabhan A, Clay-Falcone D, McCluskey L, Elman L, Juhr D, Gruber PJ, Rüb U, Auburger G, Trojanowski JQ, Lee VM, Van Deerlin VM, Bonini NM, Gitler AD (2010) Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466:1069–1075

    Article  PubMed  CAS  Google Scholar 

  • Furtado S, Payami H, Lockhart PJ, Hanson M, Nutt JG, Singleton AA, Singleton A, Bower J, Utti RJ, Bird TD, de la Fuente-Fernandez R, Tsuboi Y, Klimek ML, Suchowersky O, Hardy J, Calne DB, Wszolek ZK, Farrer M, Gwinn-Hardy K, Stoessl AJ (2004) Profile of families with parkinsonism-predominant spinocerebellar ataxia type 2 (SCA2). MovDisord 19:622–629

    Article  Google Scholar 

  • Gwinn-Hardy K, Chen JY, Liu HC, Liu TY, Boss M, Seltzer W, Adam A, Singleton A, Koroshetz W, Waters C, Hardy J, Farrer M (2000) Spinocerebellar ataxia type 2 with parkinsonism in ethnic Chinese. Neurology 55:800–805

    PubMed  CAS  Google Scholar 

  • Hussey J, Lockhart PJ, Seltzer W, Wszolek ZK, Payami H, Hanson M, Gwinn-Hardy K, Farrer M (2002) Accurate determination of ataxin-2 polyglutamine expansion in patients with intermediate-range repeats. Genet Test 6:217–220

    Article  PubMed  CAS  Google Scholar 

  • Infante J, Berciano J, Volpini V, Corral J, Polo JM, Pascual J, Combarros O (2004) Spinocerebellar ataxia type 2 with levodopa-responsive parkinsonism culminating in motor neuron disease. MovDisord 19:848–852

    Article  Google Scholar 

  • Kim JM, Hong S, Kim GP, Choi YJ, Kim YK, Park SS, Kim SE, Jeon BS (2007) Importance of low-range CAG expansion and CAA interruption in SCA2 Parkinsonism. Arch Neurol 64:1510–1518

    Article  PubMed  Google Scholar 

  • Lagier-Tourenne C, Polymenidou M, Cleveland DW (2010) TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Hum Mol Genet 19:R46–R64

    Article  PubMed  CAS  Google Scholar 

  • Lee T, Li YR, Ingre C, Weber M, Grehl T, Gredal O, de Carvalho M, Meyer T, Tysnes OB, Auburger G, Gispert S, Bonini NM, Andersen PM, Gitler AD (2011) Ataxin-2 intermediate-length polyglutamine expansions in European ALS patients. Hum Mol Genet 20:1697–1700

    Article  PubMed  CAS  Google Scholar 

  • Lu CS, Wu Chou YH, Kuo PC, Chang HC, Weng YH (2004) The parkinsonian phenotype of spinocerebellar ataxia type 2. Arch Neurol 61:35–38

    Article  PubMed  Google Scholar 

  • Nanetti L, Fancellu R, Tomasello C, Gellera C, Pareyson D, Mariotti C (2009) Rare association of motor neuron disease and spinocerebellar ataxia type 2 (SCA2): a new case and review of the literature. J Neurol 256:1926–1928

    Article  PubMed  Google Scholar 

  • Payami H, Nutt J, Gancher S, Bird T, McNeal MG, Seltzer WK, Hussey J, Lockhart P, Gwinn-Hardy K, Singleton AA, Singleton AB, Hardy J, Farrer M (2003) SCA2 may present as levodopa-responsive parkinsonism. MovDisord 18:425–429

    Article  Google Scholar 

  • Shan DE, Liu RS, Sun CM, Lee SJ, Liao KK, Soong BW (2004) Presence of spinocerebellar ataxia type 2 gene mutation in a patient with apparently sporadic Parkinson’s disease: clinical implications. MovDisord 19:1357–1360

    Article  Google Scholar 

  • Silveira I, Miranda C, Guimarães L, Moreira MC, Alonso I, Mendonça P, Ferro A, Pinto-Basto J, Coelho J, Ferreirinha F, Poirier J, Parreira E, Vale J, Januário C, Barbot C, Tuna A, Barros J, Koide R, Tsuji S, Holmes SE, Margolis RL, Jardim L, Pandolfo M, Coutinho P, Sequeiros J (2002) Trinucleotide repeats in 202 families with ataxia: a small expanded (CAG)n allele at the SCA17 locus. Arch Neurol 59:623–629

    Google Scholar 

  • Sobczak K, Krzyzosiak WJ (2005) CAG repeats containing CAA interruptions form branched hairpin structures in spinocerebellar ataxia type 2 transcripts. J BiolChem 280:3898–3910

    CAS  Google Scholar 

  • Yu Z, Zhu Y, Chen-Plotkin AS, Clay-Falcone D, McCluskey L, Elman L, Kalb RG, Trojanowski JQ, Lee VM, Van Deerlin VM, Gitler AD, Bonini NM (2011) PolyQ repeat expansions in ATXN2 associated with ALS are CAA interrupted repeats. PLoS One 6:e17951

    Google Scholar 

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Acknowledgments

We thank the patients and their families for their participation. SD was financed by RegionePiemonte (Ricerca Sanitaria Finalizzata Project-Grant 2006/Grant 2008). LC by a fellowship from “Amico Canobio” Association. We thank Joe Haining for editing the manuscript.

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Authors and Affiliations

  1. Department of Medical Sciences, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Via Solaroli, 17, 28100, Novara, Italy

    Lucia Corrado, Bernadetta Luciano, Michela Godi & Sandra D’Alfonso

  2. Department of Neurology, A. Avogadro University and Maggiore della Carità Hospital, Novara, Italy

    Letizia Mazzini & Gaia Donata Oggioni

  3. Department of Genetics Biology and Biochemistry, Università degli Studi di Torino, Torino, Italy

    Alfredo Brusco

  4. S.C.d.U. Medical Genetics, A.O.U. San Giovanni Battista, Torino, Italy

    Alfredo Brusco

  5. Biotecnologie per la Ricerca Medica Applicata (BRMA), University of Eastern Piedmont, Via Solaroli, 17, 28100, Novara, Italy

    Sandra D’Alfonso

Authors
  1. Lucia Corrado
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  2. Letizia Mazzini
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  3. Gaia Donata Oggioni
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  4. Bernadetta Luciano
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  5. Michela Godi
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  6. Alfredo Brusco
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  7. Sandra D’Alfonso
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Corresponding author

Correspondence to Lucia Corrado.

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A. Brusco and S. D’Alfonso are joint senior authors.

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Corrado, L., Mazzini, L., Oggioni, G.D. et al. ATXN-2 CAG repeat expansions are interrupted in ALS patients. Hum Genet 130, 575–580 (2011). https://doi.org/10.1007/s00439-011-1000-2

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  • DOI: https://doi.org/10.1007/s00439-011-1000-2

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