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

• Published in: Human genetics Vol. 131; no. 4; pp. 625 - 638
• Main Authors: Laffita-Mesa, José Miguel, Bauer, Peter O., Kourí, Vivian, Peña Serrano, Leodani, Roskams, Jane, Almaguer Gotay, Dennis, Montes Brown, Julio Cesar, Martínez Rodríguez, Pedro Ariel, González-Zaldívar, Yanetza, Almaguer Mederos, Luís, Cuello-Almarales, Dany, Aguiar Santiago, Jorge
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.04.2012; Springer; Springer Nature B.V
• Subjects: Adolescent; Adult; Age; Amyotrophic lateral sclerosis; Ataxin-3; Ataxins; Base Sequence; Biomedical and Life Sciences; Biomedicine; CpG islands; CpG Islands - genetics; DNA; DNA Methylation; Epigenesis, Genetic; Epigenetic inheritance; Epigenetics; Family Health; Female; Frontotemporal dementia; Gene expression; Gene Function; Genes; Homozygotes; Human Genetics; Humans; Male; Metabolic Diseases; Methylation; Middle Aged; Molecular Medicine; Molecular Sequence Data; Movement disorders; Nerve Tissue Proteins - genetics; Neurodegenerative diseases; Nuclear Proteins - genetics; Original Investigation; Parkinson's disease; Pedigree; Polymerase Chain Reaction; Promoter Regions, Genetic - genetics; Promoters; Purines; Repressor Proteins - genetics; Sequence Homology, Nucleic Acid; Spinocerebellar ataxia; Spinocerebellar Ataxias - genetics; Spinocerebellar Ataxias - pathology; trinucleotide repeat diseases; Trinucleotide Repeat Expansion - genetics; Mutant ATXN2; Atxn2 Gene; SCA2 Family; SCA2 Patient; Methylation Status
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-011-1101-y

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.