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Epigenetics DNA methylation in the core ataxin-2 gene promoter: novel physiological and pathological implications

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Abstract

Pathogenic CAG (cytosine-adenine-guanine) expansions beyond certain thresholds in the ataxin-2 (ATXN2) gene cause spinocerebellar ataxia type 2 (SCA2) and were shown to contribute to Parkinson disease, amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Regulation of ATXN2 gene expression and the function of the protein product are not known. SCA2 exhibits an inverse correlation between the size of the CAG repeat and the age at disease onset. However, a wide range of age at onset are typically observed, with CAG repeat number alone explaining only partly this variability. In this study, we explored the hypothesis that ATXN2 levels could be controlled by DNA methylation and that the derangement of this control may lead to escalation of disease severity and influencing the age at onset. We found that CpG methylation in human ATXN2 gene promoter is associated with pathogenic CAG expansions in SCA2 patients. Different levels of methylation in a SCA2 pedigree without an intergenerational CAG repeat instability caused the disease anticipation in a SCA2 family. DNA methylation also influenced the disease onset in SCA2 homozygotes and SCA3 patients. In conclusion, our study points to a novel regulatory mechanism of ATXN2 expression involving an epigenetic event resulting in differential disease course in SCA2 patients.

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Acknowledgments

We are indebted to our Cuban patients. We would like to thank Dr. Guadalupe Guzman for providing real-time PCR and other facilities at IPK. Support of Dr Ocilia Rodriguez is acknowledged. We also thank all members belonging to the Dr. Vivian Kourí laboratory for their help and expertise in real-time PCR. Acknowledgement also belongs to our colleagues from Neurobiology Department and Dr Velázquez-Pérez for his support. This work was supported in part by Third World Academy of Sciences (TWAS) in the framework of the Research Grant Project 06-329 RG/BIO/LA UNESCO FR: 3240157855, a BIOLABS Research Award and a grant of the Cuban Ministry of Health and the Science and Technology Ministry all to JMLM.

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Authors and Affiliations

  1. Center for Research and Rehabilitation of Hereditary Ataxia, CIRAH, Carlos Juan Finlay, Carretera Central Vía Habana km 51/2, Reparto Edecio Pérez, CP 80100, Holguín, Cuba

    José Miguel Laffita-Mesa, Leodani Peña Serrano, Dennis Almaguer Gotay, Yanetza González-Zaldívar, Luís Almaguer Mederos & Dany Cuello-Almarales

  2. Virology Department, Institute of Tropical Medicine “Pedro Kourí”, Autopista Novia del Mediodía, km 6½, La Lisa, PO Box 601, Marianao, Havana, 13, Cuba

    Vivian Kourí & Pedro Ariel Martínez Rodríguez

  3. Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan

    Peter O. Bauer

  4. Department of Zoology, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada

    Jane Roskams

  5. Division of Pharmaceutics, Department of Gene Therapy, Center for Genetic Engineering and Biotechnology (CIGB), Ave 31 Between 158 and 190, CP 10 600, Havana, Havana, Cuba

    Jorge Aguiar Santiago

  6. Clinical and Surgical Hospital Ernesto Guevara, Las Tunas, Cuba

    Julio Cesar Montes Brown

Authors
  1. José Miguel Laffita-Mesa
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  2. Peter O. Bauer
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  3. Vivian Kourí
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  4. Leodani Peña Serrano
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  5. Jane Roskams
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  6. Dennis Almaguer Gotay
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  7. Julio Cesar Montes Brown
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  8. Pedro Ariel Martínez Rodríguez
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  9. Yanetza González-Zaldívar
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  10. Luís Almaguer Mederos
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  11. Dany Cuello-Almarales
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  12. Jorge Aguiar Santiago
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Corresponding author

Correspondence to José Miguel Laffita-Mesa.

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Laffita-Mesa, J.M., Bauer, P.O., Kourí, V. et al. Epigenetics DNA methylation in the core ataxin-2 gene promoter: novel physiological and pathological implications. Hum Genet 131, 625–638 (2012). https://doi.org/10.1007/s00439-011-1101-y

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