Journal Article (Letter)

DZNE-2024-00566

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png A GGC-repeat expansion in ZFHX3 encoding polyglycine causes spinocerebellar ataxia type 4 and impairs autophagy

Figueroa, K. P. ; Gross, C. ; Buena-Atienza, E. ; Paul, S. ; Gandelman, M. ; Kakar, N. ; Sturm, M. ; Casadei, N. ; Admard, J. ; Park, J. ; Zühlke, C. ; Hellenbroich, Y. ; Pozojevic, J. ; Balachandran, S. ; Händler, K.Extern* ; Zittel, S. ; Timmann, D. ; Erdlenbruch, F. ; Herrmann, L. ; Feindt, T. ; Zenker, M. ; Klopstock, T.DZNE* ; Dufke, C. ; Scoles, D. R. ; Koeppen, A. ; Spielmann, M. ; Riess, O. ; Ossowski, S. ; Haack, T. B. ; Pulst, S. M.

2024
Macmillan Publishers Limited, part of Springer Nature London

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Please use a persistent id in citations: doi:10.1038/s41588-024-01719-5

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.

Keyword(s): Humans (MeSH) ; Autophagy: genetics (MeSH) ; Pedigree (MeSH) ; Trinucleotide Repeat Expansion: genetics (MeSH) ; Homeodomain Proteins: genetics (MeSH) ; Spinocerebellar Ataxias: genetics (MeSH) ; Male (MeSH) ; Female (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Homeodomain Proteins

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Contributing Institute(s):

1. Clinical Research (Munich) (Clinical Research (Munich))

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 30 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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