Peer-reviewedCC BYActa neuropathologica
SNP rs11618521 modifies transcription factor NANOG-mediated expression of KPNA3 and the age at onset of spinocerebellar ataxia type 3.
19 affiliations
- 1Institute of Medical Genetics and Applied Genomics, University of Tübingen, Nägelestraße 5, 72076, Tübingen, Germany.
- 2Department of Human Genetics, Ruhr University Bochum, 44801, Bochum, Germany.
- 3Department of Clinical Epidemiology and Applied Biometry, University of Tübingen, 72076, Tübingen, Germany.
- 4Department of Neurology, Meir Medical Center, Tel Aviv University, 69978, Tel Aviv, Israel.
- 5Universidade Estadual de Campinas (UNICAMP), Campinas, 13083-970, Brazil.
- 6Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Porto Alegre, 90035-903, Brazil.
- 7Departamento de Bioquímica, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, 90035-003, Brazil.
- 8Centros de Pesquisa Clínica E Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, 90035‑903, Brazil.
- 9Departamento de Medicina Interna, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, 90035-903, Brazil.
- 10Neurogenetics Working Group, Universidad Científica del Sur, 15067, Lima, Peru.
- 11Neurogenetics Research Center, Instituto Nacional de Ciencias Neurológicas, 15003, Lima, Peru.
- 12Centogene GmbH, 18055, Rostock, Germany.
- 13Pomeranian Medical University PUM, 70-204, Szczecin, Poland.
- 14Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076, Tübingen, Germany.
- 15German Center of Neurodegenerative Diseases (DZNE), 72076, Tübingen, Germany.
- 16Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, 6525, Nijmegen, Netherlands.
- 17Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France.
- 18German Center for Neurodegenerative Diseases (DZNE), 53127, Bonn, Germany.
- 19Institute of Medical Genetics and Applied Genomics, University of Tübingen, Nägelestraße 5, 72076, Tübingen, Germany. [email protected].
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.
Related
- Lack of tau expression modifies epileptogenesis associated neuroplasticity in the ventral dentate gyrus in a mouse model of temporal lobe epilepsy
- Coronavirus Nsp5‑mediated dual‑site cleavage of GSDMA modifies its antiviral and proinflammatory functions
- Multi‐Omics Analysis Uncovers the Salicylic Acid and Ethylene‐Responsive Transcription Factor‐Mediated Defence Mechanism of Panax notoginseng to Panax notoginseng Virus Y
- Indole induces intestinal T helper-17 cell overproduction during inflammatory bowel disease through PKA/SP1-mediated Trim21 transcription
- The kinetoplastid-specific transcription factor mtTF1 is essential for mitochondrial gene expression and maxicircle replication in Trypanosoma brucei
BibTeX
@article{han2026rs11618521,
title = {{SNP rs11618521 modifies transcription factor NANOG-mediated expression of KPNA3 and the age at onset of spinocerebellar ataxia type 3.}},
author = {Hezhou Han and Leah Czisch and Manuel Pascal Wanner and Jonasz Jeremiasz Weber and Miriam Christina Dieterle and Carolina Alexandra Licia Schroeder and Pengfei Qi and Junbo Zhou and Jaqueline Jung and Wenxu Zheng and Fubo Cheng and Priscila Pereira Sena and Florian Fath and Gunnar Blumenstock and Carlos R Gordon and Roy Zaltzman and Marcondes C França and Maria-Luiza Saraiva-Pereira and Laura Bannach Jardim and Mario R Cornejo-Olivas and Peter Bauer and Ludger Schöls and Bart P C van de Warrenburg and Alexandra Durr and Alexis Brice and Thomas Klockgether and Olaf Riess and EUROSCA Network and Thorsten Schmidt},
journal = {Acta neuropathologica},
year = {2026},
month = oct,
doi = {10.1007/s00401-026-03051-0},
url = {https://europepmc.org/article/MED/42961534},
note = {CC BY},
}
RIS
TY - JOUR
TI - SNP rs11618521 modifies transcription factor NANOG-mediated expression of KPNA3 and the age at onset of spinocerebellar ataxia type 3.
AU - Hezhou Han
AU - Leah Czisch
AU - Manuel Pascal Wanner
AU - Jonasz Jeremiasz Weber
AU - Miriam Christina Dieterle
AU - Carolina Alexandra Licia Schroeder
AU - Pengfei Qi
AU - Junbo Zhou
AU - Jaqueline Jung
AU - Wenxu Zheng
AU - Fubo Cheng
AU - Priscila Pereira Sena
AU - Florian Fath
AU - Gunnar Blumenstock
AU - Carlos R Gordon
AU - Roy Zaltzman
AU - Marcondes C França
AU - Maria-Luiza Saraiva-Pereira
AU - Laura Bannach Jardim
AU - Mario R Cornejo-Olivas
AU - Peter Bauer
AU - Ludger Schöls
AU - Bart P C van de Warrenburg
AU - Alexandra Durr
AU - Alexis Brice
AU - Thomas Klockgether
AU - Olaf Riess
AU - EUROSCA Network
AU - Thorsten Schmidt
PY - 2026
DA - 2026/10/30
JO - Acta neuropathologica
DO - 10.1007/s00401-026-03051-0
UR - https://europepmc.org/article/MED/42961534
AB - 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.
SN - 0001-6322
SN - 1432-0533
ER -