Epigenetics DNA methylation in the core ataxin-2 gene promoter: novel physiological and pathological implications.
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.
Center for Research and Rehabilitation of Hereditary Ataxia, CIRAH, Carlos Juan Finlay, Reparto Edecio Pérez, Holguín, Cuba. laffita@ataxia.hlg.sld.cu
José Miguel
JM
Laffita-Mesa
Peter O
PO
Bauer
Vivian
V
Kourí
Leodani
L
Peña Serrano
Jane
J
Roskams
Dennis
D
Almaguer Gotay
Julio Cesar
JC
Montes Brown
Pedro Ariel
PA
Martínez Rodríguez
Yanetza
Y
González-Zaldívar
Luís
L
Almaguer Mederos
Dany
D
Cuello-Almarales
Jorge
J
Aguiar Santiago
D000293:Adolescent; D000328:Adult; D000067699:Ataxin-3; D000067528:Ataxins; D001483:Base Sequence; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005192:Family Health; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000473:pathology; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
D000067528:Ataxins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C092341:ATXN3 protein, human; D000067699:Ataxin-3