Journal Article

DZNE-2026-01133

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png SNP rs11618521 modifies transcription factor NANOG-mediated expression of KPNA3 and the age at onset of spinocerebellar ataxia type 3.

Han, H. ; Czisch, L. ; Wanner, M. P. ; Weber, J. J. ; Dieterle, M. C. ; Schroeder, C. A. L. ; Qi, P. ; Zhou, J. ; Jung, J. ; Zheng, W. ; Cheng, F. ; Pereira Sena, P. ; Fath, F. ; Blumenstock, G. ; Gordon, C. R. ; Zaltzman, R. ; França, M. C. ; Saraiva-Pereira, M.-L. ; Jardim, L. B. ; Cornejo-Olivas, M. R. ; Bauer, P. ; Schöls, L.DZNE* ; van de Warrenburg, B. P. C. ; Durr, A. ; Brice, A. ; Klockgether, T.DZNE* ; Riess, O. ; Network, E. (Collaboration Author) ; Schmidt, T.

2026
Springer Heidelberg

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Please use a persistent id in citations: doi:10.1007/s00401-026-03051-0

Abstract: Intranuclear localization of the affected protein ataxin-3 is critical for the pathogenesis of spinocerebellar ataxia type 3 (SCA3). The nuclear-cytoplasmic transporter karyopherin alpha 3 (KPNA3) has been demonstrated to play an essential role in the pathophysiology of this disorder. In this study, we characterized the single nucleotide polymorphism (SNP) rs11618521, located in the KPNA3 promoter, as a genetic modifier of the age at onset in SCA3 and a regulator of the KPNA3 promoter activity. Moreover, we identified the transcription factor Nanog homeobox (NANOG) as a key regulator exerting allele-specific modulatory effects on the KPNA3 promoter activity, thereby modulating expression and contributing to SCA3-associated pathogenic mechanisms. Pharmacological inhibition of NANOG reduced KPNA3 levels and ameliorated aggregate formation. In conclusion, we identified variant rs11618521 as a regulator of KPNA3 promoter activity and as a genetic modifier of SCA3. Moreover, we provide mechanistic insights that may guide future-targeted therapeutic strategies.

Keyword(s): Humans (MeSH) ; alpha Karyopherins: genetics (MeSH) ; alpha Karyopherins: metabolism (MeSH) ; Polymorphism, Single Nucleotide: genetics (MeSH) ; Machado-Joseph Disease: genetics (MeSH) ; Machado-Joseph Disease: metabolism (MeSH) ; Machado-Joseph Disease: pathology (MeSH) ; Promoter Regions, Genetic (MeSH) ; Age of Onset (MeSH) ; Homeodomain Proteins: genetics (MeSH) ; Homeodomain Proteins: metabolism (MeSH) ; Animals (MeSH) ; Nanog Homeobox Protein (MeSH) ; Amcasertib ; Importin alpha 4 ; Karyopherin alpha 3 ; Machado–Joseph disease ; Neurodegeneration ; Polyglutamine (polyQ) ; Transcription factor ; alpha Karyopherins ; KPNA3 protein, human ; NANOG protein, human ; Homeodomain Proteins ; Nanog Homeobox Protein

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Contributing Institute(s):

1. Clinical Neurogenetics (AG Schöls)
2. Patient Studies (Bonn) (Patient Studies (Bonn))

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2026

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Springer ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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