Journal Article

A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy

Feindt, Thomas, Ossowski, Stephan, Scoles, Daniel R., Gross, Caspar, Balachandran, Saranya, Admard, Jakob, Buena-Atienza, Elena, Sturm, Marc, Zühlke, Christine, Riess, Olaf, Spielmann, Malte, Pulst, Stefan M., Figueroa, Karla P., Hellenbroich, Yorck, Park, Joohyun, Paul, Sharan, Zenker, Martin, Klopstock, Thomas, Pozojevic, Jelena, Herrmann, Laura, Gandelman, Mandi, Timmann, Dagmar, Haack, Tobias B., Dufke, Claudia, Händler, Kristian, Erdlenbruch, Friedrich, Koeppen, Arnulf, Kakar, Naseebullah, Zittel, Simone, Casadei, Nicolas

2024

Overview

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. Long-read sequencing identifies a GGC-repeat expansion in the coding region of ZFHX3 as the cause of spinocerebellar ataxia type 4. The expansion encodes polyglycine and results in intranuclear aggregates and abnormal autophagy.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/2489/1512 / 692/699/375/365/1917 / Agriculture / Algorithms / Animal Genetics and Genomics / Ataxia / Atrophy / Autophagy / Autophagy - genetics / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cerebellar ataxia / Cerebellum / Datasets / DNA repeat expansion / DNA sequencing / Female / Fibroblasts / Gene Function / Gene sequencing / Genomes / Haplotypes / Homeobox / Homeodomain Proteins - genetics / Human Genetics / Humans / Induced Pluripotent Stem Cells - metabolism / Letter / Male / Pedigree / Pluripotency / Proteins / siRNA / Spinocerebellar ataxia / Spinocerebellar Ataxias - genetics / Stem cells / Transcription factors / Trinucleotide Repeat Expansion - genetics / Ubiquitin / Whole genome sequencing / Zinc finger proteins