Modeling ATN1 mutations in human iPSCs reveals early developmental roles of atrophin-1
- 1Institute of Bioorganic Chemistry Polish Academy of Sciences
Abstract
Atrophin-1 (ATN1), encoded by the ATN1 gene, is an evolutionarily conserved transcriptional corepressor implicated in neuronal development and severe incurable disorders, including the polyglutamine (polyQ) disease - dentatorubral-pallidoluysian atrophy (DRPLA), and the neurodevelopmental syndrome CHEDDA. However, the cellular function of ATN1 and its role during early human development remain largely uncharacterized. Here, we generated an isogenic panel of human induced pluripotent stem cell (iPSC) lines, establishing a novel resource for comprehensive studies of ATN1 function and dysfunction. This panel includes a DRPLA patient-derived line (wt/mut), CRISPR-Cas9-corrected wild-type controls (wt/wt), complete ATN1 knock-out clones (-/-), and heterozygous lines expressing either a wild-type or a mutant allele (wt/- and -/mut). While pluripotency markers remained unaffected across all variants, further characterization revealed marked proliferation deficits in ATN1 knock-out lines and heterozygous iPSCs without wild-type allele expression. Moreover, the formation of punctate ATN1 assemblies was enhanced in iPSCs with -/mut variants. The pronounced phenotype observed in cells expressing only the mutant ATN1 allele may result from a combination of loss-of-function and toxic gain-of-function mechanisms. Overall, the generated panel of iPSC lines provides a unique cellular platform for investigating ATN1-dependent molecular mechanisms and their contribution to neuronal development and disease.
Related
- Genomic structural equation modeling reveals a common genetic dimension contributing to variation in growth‑related traits across multiple developmental stages
- Modeling of human MLH1 and MLH3 variants in mice reveals novel functions of MutLγ in meiotic DNA repair and the ovarian reserve
- Population connective field modeling reveals proto-retinotopic visual cortex organization in the prenatal human brain
- Single Cell Proteomics reveals partial uncoupling of the Glycerol-3-Phosphate shuttle to compensate for Electron Transport Chain dysfunction in Alexander Disease GFAP mutations
- Network topology reveals distinct forms of developmental leverage in the Drosophila wing
BibTeX
@misc{kozlowska2026modeling,
title = {{Modeling ATN1 mutations in human iPSCs reveals early developmental roles of atrophin-1}},
author = {E. Kozlowska and N. Ziojla and B. Nowak and P. Joachimiak and M. Dabrowska-Maroszek and M. Sikora and O. Brodka and M. Olejniczak and A. Fiszer},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.30.760413},
url = {https://www.biorxiv.org/content/10.64898/2026.10.30.760413v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Modeling ATN1 mutations in human iPSCs reveals early developmental roles of atrophin-1
AU - E. Kozlowska
AU - N. Ziojla
AU - B. Nowak
AU - P. Joachimiak
AU - M. Dabrowska-Maroszek
AU - M. Sikora
AU - O. Brodka
AU - M. Olejniczak
AU - A. Fiszer
PY - 2026
DA - 2026/10/30
PB - bioRxiv
DO - 10.64898/2026.10.30.760413
UR - https://www.biorxiv.org/content/10.64898/2026.10.30.760413v1
AB - Atrophin-1 (ATN1), encoded by the ATN1 gene, is an evolutionarily conserved transcriptional corepressor implicated in neuronal development and severe incurable disorders, including the polyglutamine (polyQ) disease - dentatorubral-pallidoluysian atrophy (DRPLA), and the neurodevelopmental syndrome CHEDDA. However, the cellular function of ATN1 and its role during early human development remain largely uncharacterized. Here, we generated an isogenic panel of human induced pluripotent stem cell (iPSC) lines, establishing a novel resource for comprehensive studies of ATN1 function and dysfunction. This panel includes a DRPLA patient-derived line (wt/mut), CRISPR-Cas9-corrected wild-type controls (wt/wt), complete ATN1 knock-out clones (-/-), and heterozygous lines expressing either a wild-type or a mutant allele (wt/- and -/mut). While pluripotency markers remained unaffected across all variants, further characterization revealed marked proliferation deficits in ATN1 knock-out lines and heterozygous iPSCs without wild-type allele expression. Moreover, the formation of punctate ATN1 assemblies was enhanced in iPSCs with -/mut variants. The pronounced phenotype observed in cells expressing only the mutant ATN1 allele may result from a combination of loss-of-function and toxic gain-of-function mechanisms. Overall, the generated panel of iPSC lines provides a unique cellular platform for investigating ATN1-dependent molecular mechanisms and their contribution to neuronal development and disease.
ER -