A GGC-repeat expansion in ZFHX3 causes spinocerebellar ataxia type 4

Despite the significant advances in the knowledge of hereditary ataxias, some of their causative mutations and disease mechanisms still remain uncharacterized. That was the case in spinocerebellar ataxia type 4 (SCA4), a slowly progressive adult-onset autosomal dominant ataxia frequently associated with peripheral neuropathy, dysphagia and dysautonomia. Cronic cough was also a feature in some individuals.
In a recently published study, Figueroa et al. used long-read sequencing approaches to further advance the knowledge regarding the specific mutation and possible pathogenic mechanisms of SCA4.¹
The authors identified a dominant GGC repeat expansion in the final coding exon of the ZFHX3 gene, predicted to be translated into a toxic polyglicine-containing variant protein.¹ This finding was further supported by concomitant independent findings from three other groups.²
Zinc finger homeobox protein 3 (ZFHX3) is an abundantly expressed trancription factor implicated in tumor supression and as a risk factor for atrial fibrillation. Loss-of-function ZFHX3 mutations lead to a neurodevelopmental phenotype, with intellectual disability and facial dysmorphisms, who does not occur in SCA4.
Regarding disease pathology, the polyglicine-containing protein that results from the expansion was expressed in fibroblasts from a patient with SCA4 and accumulated in the ubiquitin-positive intranuclear inclusions typical of SCA4 present in the brain of a patient.¹ These findings are similar to those encountered in other GGC expansion disorders (fragile-X associated tremor/ataxia syndrome - FXTAS - and neuronal intranuclear inclusion disease  - NIID).
With this discovery, SCA4 can be included in the group of polyglicine disorders, which includes not only FXTAS and NIID, but also oculopharyngeal muscular dystrophy (OPMD). However, this expansion has some particularities, namely a smaller number of repeats (> 40), its location in a coding exon and the function of the gene product as a transcription factor.¹
The findings of this study further highlight the importance and future possibilities of long read sequencing approaches coupled with bioinformatics to discover causative mutations for neurological disorders, like CANVAS, SCA27b, C9Orf72 related disorders and now SCA4.

Key Points:

• SCA4 is an adult-onset autosomal dominant ataxia frequently associated with peripheral neuropathy, dysphagia and dysautonomia.
• A GGC repeat expansion in the ZFHX3 gene, translated into a toxic polyglicine-containing protein, was identified as the causative mutation for SCA4.
• The resulting protein accumulates in ubiquitin-positive intranuclear inclusions in the brain, a mechanism similar to other polyglicine expansion disorders.
• Other pathogenic polyglicine expansion disorders may remain unidentified in complex GC-rich regions.

References:

1. Figueroa KP, Gross C, Buena-Atienza E, et al. A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy. Nat Genet. 2024;56(6):1080-1089. doi:10.1038/s41588-024-01719-5
2. Charlet-Berguerand N. An unexpected polyglycine route to spinocerebellar ataxia. Nat Genet. 2024;56(6):1039-1041. doi:10.1038/s41588-024-01770-2

Co-authors:

• Michelangelo Mancuso, Neurological Institute, University of Pisa
• Kailash Bhatia, UCL Queen Square Institute of Neurology, University College London

Publish on behalf of the Coordinating Panel on Rare Neurological Disease