SCA4_ZFHX3
- Gene
- ZFHX3
- Disease
- SCA4
- Inheritance
- AD
- Classification
- Definitive
- Total Score
- 13.5
- Publications Reviewed
- 7
- Publication Span
- 22.08 years
- Last Updated
- 08/18/2025
- Curator(s)
- Macayla Weiner, Laurel Hiatt
Description
Heterozygous exonic GGC repeat expansions in the final coding exon of ZFHX3, encoding an expanded polyglycine tract, cause autosomal dominant spinocerebellar ataxia type 4 (SCA4). The locus-disease relationship is supported by multiple affected families with cerebellar ataxia and sensory neuropathy, segregation/linkage to the 16q22 SCA4 region, pathogenic-range uninterrupted GGC expansions absent from large control datasets, and repeat-length effects on age at onset and severity. Experimental evidence includes ZFHX3/p62/ubiquitin-positive neuronal inclusions, increased ZFHX3 protein abundance, impaired autophagy in patient-derived cell models, and allele-specific methylation changes at the expanded haplotype.
Genetic evidence
Total: 9.5
| Singular Evidence | Probands | PMID:38035881 | 6 | Five Swedish SCA4 probands/families with cerebellar ataxia, sensory neuropathy, and uninterrupted exonic GGC repeat expansions in ZFHX3; expansions co-segregated in the families studied and were absent from large in-house/SweGen control datasets. |
| Collective Evidence | Allele | PMID:39095619 | 2 | Expanded ZFHX3 GGC allele size correlated inversely with age at onset and supported anticipation; pathogenic alleles in the German cohort ranged from 44 to 68 repeats, with longer expansions associated with earlier onset and more severe phenotype. |
| Collective Evidence | Segregation | PMID:12796826 | 1.5 | Locus-level segregation evidence: a five-generation northern German SCA4 family showed linkage to chromosome 16q22, with affected members sharing the disease haplotype and a maximum two-point LOD score of 4.48 at D16S3018. This predates ZFHX3 GGC discovery and supports the SCA4 interval rather than directly genotyping the repeat expansion. |
Experimental evidence
Total: 4
| Function | Protein interaction | PMID:38684900 | 0.5 | Postmortem SCA4 brain tissue showed neuronal intranuclear inclusions positive for ZFHX3, p62, and ubiquitin in basis pontis neurons, supporting aggregation/association with proteostasis markers; direct biochemical protein interaction was not separately demonstrated. |
| Function | Regulatory impact | PMID:38197134 PMID:38684900 PMID:39635987 PMID:40459184 | 1.5 | Regulatory/epigenetic effects are supported across available sources: ZFHX3 expression in nervous-system tissues was evaluated; SCA4 patient fibroblasts/iPSCs showed increased ZFHX3 protein without increased mRNA; and long-read methylation analyses in Swedish/Utah/Iowa and Chilean carriers showed allele-specific hypermethylation of the repeat-containing haplotype. |
| Functional Alteration | Patient cells | PMID:38684900 | 1 | Patient-derived fibroblasts and induced pluripotent stem cells carrying the ZFHX3 GGC expansion showed increased ZFHX3 protein abundance and increased autophagy markers including p-mTOR, mTOR, p62, and LC3-II, consistent with impaired autophagy. |
| Models | Cell culture | PMID:38684900 | 1 | Cultured patient-derived fibroblast and iPSC models showed abnormal autophagy that was normalized after siRNA-mediated ZFHX3 knockdown, supporting a cell-culture disease model and a ZFHX3-dependent effect. |
Note: Maximum score caps apply at evidence type, category, and supercategory levels, so section totals may be lower than the raw sum of row scores.