ArticleNature genetics2024
A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy.
Article in Nature genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers, 1 of them a synthesis that pooled it.
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Who cites it
29 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Epidemiology of Autosomal Dominant Spinocerebellar Ataxias in Latin America: A Systematic Review and Meta-Analysis.Cerebellum (London, England) · 2025Pooled it
- Structural Polymorphism of polyG Inclusions Revealed by In Situ Cryo-Electron Tomography.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Large-scale genetic profiling of hereditary ataxias in China: implications for a stepwise molecular diagnostic strategy.Translational neurodegeneration · 2026Article
- Long-read sequencing reveals a hidden Alu-mediated splice defect in CPLANE1, causing orofaciodigital syndrome type VI.European journal of human genetics : EJHG · 2026Article
- Toward the clinical application of long-read sequencing in repeat-expansion disorders.Nature genetics · 2026Review
- Frequency of ZFHX3-Mediated Spinocerebellar Ataxia 4 in a US Undiagnosed Ataxia Cohort.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- CGG Repeat Expansion in GIPC1 is Associated with Childhood-Onset Hereditary Ataxia.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- Genetically informed dissection of multimodal brain aging and ten major psychiatric disorders.Molecular psychiatry · 2026Article
- Computational Short Tandem Repeat Genotyping Reveals Clinically Relevant Expansions in a Large Turkish Neurodegeneration Disease Cohort.International journal of molecular sciences · 2026Article
- Repeat-associated ataxias in a German patient cohort analysed by targeted parallel long-read sequencing.Brain : a journal of neurology · 2026Article
- Identification of de novo variants from parent-proband duos via long-read sequencing.American journal of human genetics · 2026Article
- 'Non-coding' GGC repeats are translated into toxic polyglycine proteins in neuromuscular diseases.Nature genetics · 2026Article
- GGC repeat expansions within new open reading frames are translated into toxic polyglycine proteins in oculopharyngodistal myopathy.Nature genetics · 2026Article
- Precise excision of expanded GGC repeats in NOTCH2NLC via CRISPR/Cas9 for treating neuronal intranuclear inclusion disease.Nature communications · 2026Article
- A CGG Repeat Expansion in CSNK1E Associated with Progressive Myoclonic Epilepsy with Incomplete Penetrance.Movement disorders : official journal of the Movement Disorder Society · 2025Article
- Identification of GGC Repeat Expansions in ZFHX3 among Chilean Movement Disorder Patients.Movement disorders : official journal of the Movement Disorder Society · 2025Article
- Exploration of Neurodegenerative Diseases Using Long-Read Sequencing and Optical Genome Mapping Technologies.Movement disorders : official journal of the Movement Disorder Society · 2025Review
- Biomarkers in Spinocerebellar Ataxias.Cerebellum (London, England) · 2025Review
- Long-Read Sequencing Identifies Mosaic Sequence Variations in Friedreich's Ataxia-GAA Repeats.International journal of molecular sciences · 2025Article
- Repeat expansion disorders.Practical neurology · 2025Review
Corrections and comments
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Authors and funding
30 authors.
Funding
Abstract
Despite linkage to chromosome 16q in 1996, the mutation causing spinocerebellar ataxia type 4 (SCA4), a late-onset sensory and cerebellar ataxia, remained unknown. Here, using long-read single-strand whole-genome sequencing (LR-GS), we identified a heterozygous GGC-repeat expansion in a large Utah pedigree encoding polyglycine (polyG) in zinc finger homeobox protein 3 (ZFHX3), also known as AT-binding transcription factor 1 (ATBF1). We queried 6,495 genome sequencing datasets and identified the repeat expansion in seven additional pedigrees. Ultrarare DNA variants near the repeat expansion indicate a common distant founder event in Sweden. Intranuclear ZFHX3-p62-ubiquitin aggregates were abundant in SCA4 basis pontis neurons. In fibroblasts and induced pluripotent stem cells, the GGC expansion led to increased ZFHX3 protein levels and abnormal autophagy, which were normalized with small interfering RNA-mediated ZFHX3 knockdown in both cell types. Improving autophagy points to a therapeutic avenue for this novel polyG disease. The coding GGC-repeat expansion in an extremely G+C-rich region was not detectable by short-read whole-exome sequencing, which demonstrates the power of LR-GS for variant discovery.
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