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CC BY-NC-ND 4.0 · Arq Neuropsiquiatr 2019; 77(02): 73-79
DOI: 10.1590/0004-282X20190006
Article

GBA mutations p.N370S and p.L444P are associated with Parkinson's disease in patients from Northern Brazil

Mutações p.N370S e p.L444P no gene GBA estão associadas com doença de Parkinson em pacientes do norte do Brasil
Carlos Eduardo de Melo Amaral
1   Universidade Federal do Pará, Laboratório de Erros Inatos de Metabolismo, Belém PA, Brasil;
,
Patrick Farias Lopes
1   Universidade Federal do Pará, Laboratório de Erros Inatos de Metabolismo, Belém PA, Brasil;
,
Juliana Cristina Cardoso Ferreira
1   Universidade Federal do Pará, Laboratório de Erros Inatos de Metabolismo, Belém PA, Brasil;
,
Erik Artur Cortinhas Alves
1   Universidade Federal do Pará, Laboratório de Erros Inatos de Metabolismo, Belém PA, Brasil;
,
Marcella Vieira Barroso Montenegro
1   Universidade Federal do Pará, Laboratório de Erros Inatos de Metabolismo, Belém PA, Brasil;
,
Edmar Tavares da Costa
3   Universidade Federal do Pará, Laboratório de Neuropatologia Experimental, Belém PA, Brasil.
,
Elizabeth Sumi Yamada
3   Universidade Federal do Pará, Laboratório de Neuropatologia Experimental, Belém PA, Brasil.
,
Fernando Otávio Quaresma Cavalcante
2   Universidade Federal do Pará, Hospital Universitário João Barros de Barreto, Belém PA, Brasil;
,
Luiz Carlos Santana-da-Silva 
1   Universidade Federal do Pará, Laboratório de Erros Inatos de Metabolismo, Belém PA, Brasil;
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ABSTRACT

Mutations of the GBA gene have been reported in patients with Parkinson's disease (PD) from a number of different countries, including Brazil. In order to confirm this pattern in a sample of PD patients from northern Brazil, we conducted a case-control study of the occurrence of the two most common mutations of the GBA gene (c.1226A>G; p.N370S and c.1448T>C; p.L444P) in a group of 81 PD patients and 81 control individuals, using PCR-RFLP, confirmed by the direct sequencing of the PCR products. In the patient group, three patients (3.7%) were heterozygous for the GBA c.1226A>G; p.N370S mutation, and three (3.7%) for GBA c.1448T>C; p.L444P Neither mutation was detected in the control group (p =0.0284). Patients with the c.1448T>C; p.L444P mutation showed a tendency to have an earlier disease onset, but a larger sample number is required to confirm this observation. Our results suggest an association between the GBA c.1226A>G; p.N370S and c.1448T>C; p.L444P mutations and the development of PD in the population of patients from the Northern Brazil.

RESUMO

Mutações no gene GBA têm sido reportadas em pacientes com doença de Parkinson (DP) em diferentes países, incluindo o Brasil. Com o objetivo de confirmar esse padrão em uma amostra de pacientes com DP provenientes do Norte brasileiro, foi conduzindo esse estudo caso-controle investigando a frequência das duas mutações mais comuns do gene GBA (c.1226A>G; p.N370S e c.1448T>C; p.L444P) em um grupo de 81 pacientes com DP e 81 controles, usando PCR-RFLP e confirmado pelo sequenciamento direto de produtos de PCR. No grupo experimental, três pacientes (3,7%) foram heterozigotos para a mutação c.1226A>G; p.N370S e três (3,7%), para a mutação c.1448T>C; p.L444P Nenhuma das duas mutações foi detectada no grupo controle (p =0,0284). Pacientes com a mutação c.1448T>C; p.L444P demonstraram uma tendência a apresentar os sintomas mais precocemente, porém um número amostrai maior é necessário para confirmar essa observação. Nossos resultados sugerem uma associação entre essas duas mutações no gene GBA e o desenvolvimento de DP na população de pacientes do norte Brasileiro.

Keywords:

Gaucher disease - mutation - Parkinson's disease

Palavras-chave:

Doença de Gaucher - mutação - doença de Parkinson

Support

Instituto Nacional de Genética Médica e Populacional - INAGEMP (CNPq: 573993/2008-4), Fundação de Amparo à Pesquisa do Estado do Pará (FAPESPA), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES).




Publication History

Received: 08 August 2018

Accepted: 21 November 2018

Article published online:
21 August 2023

© 2023. Academia Brasileira de Neurologia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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  • References

  • 1 Farrer MJ. Genetics of Parkinson disease: paradigm shifts and future prospects. Nat Rev Genet. 2006 Apr;7(4):306-18. https://doi.org/10.1038/nrg1831
  • 2 Wu YR, Chen CM, Chao CY, Ro LS, Lyu RK, Chang KH, et al. Glucocerebrosidase gene mutation is a risk factor for early onset of Parkinson disease among Taiwanese. J Neurol Neurosurg Psychiatry. 2007 Sep;78(9):977-9. https://doi.org/10.1136/jnnp.2006.105940
  • 3 McNeill A, Wu RM, Tzen KY, Aguiar PC, Arbelo JM, Barone P, et al. Dopaminergic neuronal imaging in genetic Parkinson's disease: insights into pathogenesis. PLoS One. 2013 Jul;8(7):e69190. https://doi.org/10.1371/journal.pone.0069190
  • 4 Trinh J, Farrer M. Advances in the genetics of Parkinson disease. Nat Rev Neurol. 2013 Aug;9(8):445-54. https://doi.org/10.1038/nrneurol.2013.132
  • 5 Bembi B, Zambito Marsala S, Sidransky E, Ciana G, Carrozzi M, Zorzon M, et al. Gaucher's disease with Parkinson's disease: clinical and pathological aspects. Neurology. 2003 Jul;61(1):99-101. https://doi.org/10.1212/01.WNL.0000072482.70963.D7
  • 6 Alcalay RN, Dinur T, Quinn T, Sakanaka K, Levy O, Waters C, et al. Comparison of Parkinson risk in Ashkenazi Jewish patients with Gaucher disease and GBA heterozygotes. JAMA Neurol. 2014 Jun;71(6):752-7. https://doi.org/10.1001/jamaneurol.2014.313
  • 7 Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R. Mutations in the glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews. N Engl J Med. 2004 Nov;351(19):1972-7. https://doi.org/10.1056/NEJMoa033277
  • 8 Lwin A, Orvisky E, Goker-Alpan O, LaMarca ME, Sidransky E. Glucocerebrosidase mutations in subjects with parkinsonism. Mol Genet Metab. 2004 Jan;81(1):70-3. https://doi.org/10.1016/j.ymgme.2003.11.004
  • 9 Toft M, Pielsticker L, Ross OA, Aasly JO, Farrer MJ. Glucocerebrosidase gene mutations and Parkinson disease in the Norwegian population. Neurology. 2006 Feb;66(3):415-7. https://doi.org/10.1212/01.wnl.0000196492.80676.7c
  • 10 Sidransky E, Nalls MA, Aasly JO, Aharon-Peretz J, Annesi G, Barbosa ER, et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med. 2009 Oct;361(17):1651-61. https://doi.org/10.1056/NEJMoa0901281
  • 11 Mazzulli JR, Xu YH, Sun Y, Knight AL, McLean PJ, Caldwell GA, et al. Gaucher disease glucocerebrosidase and α-synuclein form a bidirectional pathogenic loop in synucleinopathies. Cell. 2011 Jul;146(1):37-52. https://doi.org/10.1016/j.cell.2011.06.001
  • 12 Feany MB. New genetic insights into Parkinson's disease. N Engl J Med. 2004 Nov;351(19):1937-40. https://doi.org/10.1056/NEJMp048263
  • 13 Bussell R Jr, Eliezer D. Effects of Parkinson's disease-linked mutations on the structure of lipid-associated α-synuclein. Biochemistry. 2004 Apr;43(16):4810-8. https://doi.org/10.1021/bi036135+
  • 14 Clark LN, Ross BM, Wang Y, Mejia-Santana H, Harris J, Louis ED, et al. Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease. Neurology. 2007 Sep;69(12):1270-7. https://doi.org/10.1212/01.wnl.0000276989.17578.02
  • 15 Gan-Or Z, Giladi N, Rozovski U, Shifrin C, Rosner S, Gurevich T, et al. Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology. 2008 Jun;70(24):2277-83. https://doi.org/10.1212/01.wnl.0000304039.11891.29
  • 16 Gan-Or Z, Amshalom I, Kilarski LL, Bar-Shira A, Gana-Weisz M, Mirelman A, et al. Differential effects of severe vs mild GBA mutations on Parkinson disease. Neurology. 2015 Mar;84(9):880-7. https://doi.org/10.1212/WNL.20190006201900061315
  • 17 Spitz M, Rozenberg R, Pereira LV, Barbosa ER. Association between Parkinson's disease and glucocerebrosidase mutations in Brazil. Parkinsonism RelatDisord. 2008;14(1):58-62. https://doi.org/10.1016/j.parkreldis.2007.06.010
  • 18 Nichols WC, Pankratz N, Marek DK, Pauciulo MW, Elsaesser VE, Halter CA, et al.; Parkinson Study Group-PROGENI Investigators. Mutations in GBA are associated with familial Parkinson disease susceptibility and age at onset. Neurology. 2009 Jan;72(4):310-6. https://doi.org/10.1212/01.wnl.0000327823.81237.d1
  • 19 Moraitou M, Hadjigeorgiou G, Monopolis I, Dardiotis E, Bozi M, Vassilatis D, et al. β-Glucocerebrosidase gene mutations in two cohorts of Greek patients with sporadic Parkinson's disease. Mol Genet Metab. 2011 Sep-Oct;104(1-2):149-52. https://doi.org/10.1016/j.ymgme.2011.06.015
  • 20 Winder-Rhodes SE, Evans JR, Ban M, Mason SL, Williams-Gray CH, Foltynie T, et al. Glucocerebrosidase mutations influence the natural history of Parkinson's disease in a community-based incident cohort. Brain. 2013 Feb;136(Pt 2):392-9. https://doi.org/10.1093/brain/aws318
  • 21 Asselta R, Rimoldi V, Siri C, Cilia R, Guella I, Tesei S, et al. Glucocerebrosidase mutations in primary parkinsonism. Parkinsonism RelatDisord. 2014 Nov;20(11):1215-20. https://doi.org/10.1016/j.parkreldis.2014.09.003
  • 22 Lesage S, Condroyer C, Hecham N, Anheim M, Belarbi S, Lohman E, et al. Mutations in the glucocerebrosidase gene confer a risk for Parkinson disease in North Africa. Neurology. 2011 Jan;76(3):301-3. https://doi.org/10.1212/WNL.0b013e318207b01e
  • 23 Eblan MJ, Nguyen J, Ziegler SG, Lwin A, Hanson M, Gallardo M, et al. Glucocerebrosidase mutations are also found in subjects with early-onset parkinsonism from Venezuela. Mov Disord. 2006 Feb;21(2):282-3. https://doi.org/10.1002/mds.20766
  • 24 Socal MP, Bock H, Michelin-Tirelli K, Hilbig A, Saraiva-Pereira ML, Rieder CR, et al. Parkinson's disease and the heterozygous state for glucocerebrosidase mutations among Brazilians. Parkinsonism RelatDisord. 2009 Jan;15(1):76-8. https://doi.org/10.1016/j.parkreldis.2008.01.019
  • 25 Hughes AJ, Daniel SE, Lees AJ. Improved accuracy of clinical diagnosis of Lewy body Parkinson's disease. Neurology. 2001 Oct;57(8):1497-9. https://doi.org/10.1212/WNL.57.8.1497
  • 26 Guimarães BC, Pereira AC, Rodrigues FC, Santos AV, Campos Junior M, Santos JM, et al. Glucocerebrosidase N370S and L444P mutations as risk factors for Parkinson's disease in Brazilian patients. Parkinsonism RelatDisord. 2012 Jun;18(5):688-9. https://doi.org/10.1016/j.parkreldis.2011.11.028
  • 27 Rozenberg R, Araújo FT, Fox DC, Aranda P, Nonino A, Micheletti C, et al. High frequency of mutation G377S in Brazilian type 3 Gaucher disease patients. Braz J Med Biol Res. 2006 Sep;39(9):1171-9. https://doi.org/10.1590/S0100-879X2006000900004
  • 28 Bras J, Paisan-Ruiz C, Guerreiro R, Ribeiro MH, Morgadinho A, Januario C, et al. Complete screening for glucocerebrosidase mutations in Parkinson disease patients from Portugal. Neurobiol Aging. 2009 Sep;30(9):1515-7. https://doi.org/10.1016/j.neurobiolaging.2007.11.016
  • 29 Mitsui J, Mizuta I, Toyoda A, Ashida R, Takahashi Y, Goto J, et al. Mutations for Gaucher disease confer high susceptibility to Parkinson disease. Arch Neurol. 2009 May;66(5):571-6. https://doi.org/10.1001/archneurol.2009.72
  • 30 Mao XY, Burgunder JM, Zhang ZJ, An XK, Zhang JH, Yang Y, et al. Association between GBA L444P mutation and sporadic Parkinson's disease from Mainland China. Neurosci Lett. 2010 Jan;469(2):256-9. https://doi.org/10.1016/j.neulet.2009.12.007
  • 31 Santos NP, Ribeiro-Rodrigues EM, Ribeiro-Dos-Santos AK, Pereira R, Gusmão L, Amorim A, et al. Assessing individual interethnic admixture and population substructure using a 48-insertion-deletion (INSEL) ancestry-informative marker (AIM) panel. Hum Mutat. 2010 Feb;31(2):184-90. https://doi.org/10.1002/humu.21159