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

Nature Genetics (2024)Cite this article

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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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Fig. 1: Identification of the repeat expansion in ZFHX3 as causative of SCA4.
Fig. 2: Correlation of age of onset with length of the GGC-repeat region, imaging and pathological features in patients with SCA4.
Fig. 3: Fibroblasts from patients with SCA4 show elevated ZFHX3 expression.
Fig. 4: SCA4 fibroblasts show abnormal mTOR signaling and increased ATXN2 levels.
Fig. 5: Molecular phenotypes in iPS cells derived from patients with SCA4.

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Data availability

The data that support the findings of this study are available on request from the corresponding authors (S.M.P. and O.R.). The data are not publicly available as they contain information that could compromise the privacy of research participants. Source data are provided with this paper.

Code availability

(1) Open-source tools and pipelines: (1.1) in-house developed tools and pipelines: megSAP version 2022_08 (short-read WGS data): https://github.com/imgag/megSAP, https://doi.org/10.5281/zenodo.10817663 (ref. 57); megLR v1.0.0 (long-read WGS data): https://github.com/imgag/megLR, https://doi.org/10.5281/zenodo.10820153 (ref. 58); Expander (repeat expansion detection with Nanopore data): https://github.com/caspargross/expander, https://doi.org/10.5281/zenodo.10820172 (ref. 59); SCA4 project-specific scripts (scripts for data formatting, plotting, haplotype analysis and linkage analysis): https://github.com/imgag/sca4_project; (1.2) other open-source tools for long-read WGS analysis (used by in-house pipeline): trgt v0.4.0 (repeat expansion detection with long-read WGS HiFi): https://github.com/PacificBiosciences/trgt; Straglr v1.4.0 (repeat expansion detection with long-read WGS Nanopore): https://github.com/bcgsc/straglr; pbsv v2.9.0 (structural variant detection with long-read WGS HiFi): https://github.com/PacificBiosciences/pbsv; Sniffles2 v2.0.7 (structural variant detection with long-read WGS Nanopore): https://github.com/fritzsedlazeck/Sniffles; minimap2 v2.25 (long-read WGS alignment): https://github.com/lh3/minimap2; Flye v2.9.2 (genome assembly with long-read WGS): https://github.com/fenderglass/Flye; pb-assembly v1 (genome assembly with long-read WGS HiFi): https://github.com/PacificBiosciences/pb-assembly; hapdup v0.12 (haplotype phasing): https://github.com/KolmogorovLab/hapdup; hapdiff v0.8 (phased structural variant calling): https://github.com/KolmogorovLab/hapdiff; PEPPER-Margin-DeepVariant r0.8 (variant calling with long-read WGS Nanopore): https://github.com/kishwarshafin/pepper/releases/tag/r0.8. (2) Vendor software for sequencing platforms: (2.1) PacBio HiFi software platform: PacBio WGS Variant Pipeline: https://github.com/PacificBiosciences/HiFi-human-WGS-WDL; PacBio HiFi tools: https://github.com/PacificBiosciences; (2.2) ONT software: MinKNOW with Guppy basecaller: https://community.nanoporetech.com/docs/analyse; ONT basecallers: https://github.com/nanoporetech; (2.3) Illumina software (srWGS): Illumina DRAGEN Bio-IT Platform (release 4.2): https://support.illumina.com/sequencing/sequencing_software/dragen-bio-it-platform.html.

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Acknowledgements

We express our gratitude to the individuals with SCA4 and their relatives and caregivers. We thank L. Huynh, J. Hübener-Schmid, Q. Mao and the University of Utah Cell Imaging Core for their contributions. This work was supported by NIH grant R35 NS127253 to S.M.P. S.M.P. was partially supported by the Rindlisbacher Endowment for Research in Neurodegeneration. O.R. was partially supported by the Solve-RD project (European Union’s Horizon 2020 547 research and innovation program under grant agreement no. 779257). S.O. received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; OS 647/1-1). S.Z. was supported by the DFG, grant 465281508. T.B.H. was supported by the DFG, grants 418081722 and 433158657. J. Park was supported by the Else Kröner-Fresenius-Stiftung Clinician Scientist program ‘PRECISE.net’. NGS methods were performed with the support of the DFG-funded NGS Competence Center Tübingen (INST 37/1049-1). We thank our colleagues from the Clinical Long-read Genome Initiative (lonGER consortium) for valuable discussion and exchange on methodological aspects of ONT LR-GS.

Author information

Author notes

  1. These authors contributed equally: Karla P. Figueroa, Caspar Gross, Elena Buena-Atienza.

Authors and Affiliations

  1. Department of Neurology, University of Utah, Salt Lake City, UT, USA

    Karla P. Figueroa, Sharan Paul, Mandi Gandelman, Daniel R. Scoles & Stefan M. Pulst

  2. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany

    Caspar Gross, Elena Buena-Atienza, Marc Sturm, Nicolas Casadei, Jakob Admard, Joohyun Park, Claudia Dufke, Olaf Riess, Stephan Ossowski & Tobias B. Haack

  3. NGS Competence Center Tübingen, Tübingen, Germany

    Caspar Gross, Elena Buena-Atienza, Nicolas Casadei, Jakob Admard, Olaf Riess, Stephan Ossowski & Tobias B. Haack

  4. Institute of Human Genetics, University Medical Center Schleswig-Holstein, University of Lübeck and Kiel University, Lübeck, Germany

    Naseebullah Kakar, Christine Zühlke, Yorck Hellenbroich, Jelena Pozojevic, Saranya Balachandran, Kristian Händler & Malte Spielmann

  5. Department of Biotechnology, FLS&I, BUITEMS, Quetta, Pakistan

    Naseebullah Kakar

  6. Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Simone Zittel & Laura Herrmann

  7. Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, University of Duisburg-Essen, Essen, Germany

    Dagmar Timmann & Friedrich Erdlenbruch

  8. Practice of Neurology, Magdeburg, Germany

    Thomas Feindt

  9. Institute of Human Genetics, University Hospital Magdeburg and Medical Faculty, Otto-von-Guericke University, Magdeburg, Germany

    Martin Zenker

  10. Department of Neurology with Friedrich-Baur-Institute, University Hospital of Ludwig-Maximilians-Universität München, Munich, Germany

    Thomas Klopstock

  11. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany

    Thomas Klopstock

  12. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

    Thomas Klopstock

  13. Veterans Affairs Medical Center, Albany, NY, USA

    Arnulf Koeppen

  14. DZHK (German Centre for Cardiovascular Research), partner site Hamburg, Lübeck, Kiel, Lübeck, Germany

    Malte Spielmann

  15. Institute for Bioinformatics and Medical Informatics (IBMI), University of Tübingen, Tübingen, Germany

    Stephan Ossowski

  16. Clinical Neurosciences Center, University of Utah Hospitals and Clinics, Salt Lake City, UT, USA

    Stefan M. Pulst

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  1. Karla P. Figueroa
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  2. Caspar Gross
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Contributions

K.P.F., M. Spielmann, O.R., S.O., T.B.H. and S.M.P. jointly supervised the research. K.P.F., N.C. and S.M.P. conceptualized and designed the experiments. K.P.F., C.G., E.B.-A., S.P., M.G., T.B.H., N.K., J. Park, K.H., C.D. and A.K. performed the experiments. K.P.F. performed real-time PCR analyses. S.P. performed western blotting. M.G. produced iPS cells and iPS cell-derived neurons. M.G. and A.K. performed immunohistological stains. K.P.F., S.P., M.G., J. Park, D.R.S., S.O. and T.B.H. performed statistical tests. K.P.F., E.B.-A., S.P., M.G., N.K., M. Sturm, N.C., J.A., Y.H., J. Pozojevic, S.B., T.F. and S.O. performed data analyses. K.P.F., N.K., C.Z., Y.H., S.Z., D.T., F.E., L.H., M.Z., T.K., O.R. and S.M.P. contributed patient materials or patient data. K.P.F., E.B.-A., N.K., M. Sturm, N.C., J. Park, D.R.S., A.K., M. Spielmann, O.R., S.O., T.B.H. and S.M.P. contributed to writing the paper.

Corresponding authors

Correspondence to Olaf Riess or Stefan M. Pulst.

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Nature Genetics thanks Jianwen Deng, Clevio Nobrega and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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Extended data

Extended Data Table 1 P-values associated with charts in Figure 4d
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Extended Data Table 2 P-values associated with charts in Figure 5e
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Supplementary information

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Supplementary Figs. 1–5 and Tables 1 and 2.

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Source data

Source Data Fig. 2

Quantifications of histological data presented in Fig. 2.

Source Data Fig. 3

Full unprocessed blots associated with Fig. 3.

Source Data Fig. 3

Quantifications of blots presented in Fig. 3.

Source Data Fig. 4

Full unprocessed blots associated with Fig. 4.

Source Data Fig. 4

Quantifications of blots presented in Fig. 4.

Source Data Fig. 5

Full unprocessed blots associated with Fig. 5.

Source Data Fig. 5

Quantifications of blots presented in Fig. 5.

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Figueroa, K.P., 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). https://doi.org/10.1038/s41588-024-01719-5

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