GGC expansion inZFHX3causes SCA4 and impairs autophagy

Abstract

Despite linkage to 16q in 1996, the mutation for spinocerebellar ataxia type 4 (SCA4), a late-onset sensory and cerebellar ataxia, escaped detection for 25 years. Using long- read PacBio-HiFi and ONT-Nanopre sequencing and bioinformatic analysis, we identified expansion of a GGC DNA repeat in a >85% GC-rich region in exon 10 of theZFHX3gene coding for poly-glycine (polyG). In a total of 15 nuclear families from Utah and 9 from Europe, the repeat was expanded to >40 repeats in SCA4 patients accompanied by significant phenotypic variation independent of repeat size compared to the most common normal repeat size of 21 repeats. The RE event likely occurred in a frequent Swedish haplotype shared by cases from Utah and Germany. Six characteristic ultra-rare SNVs in the vicinity of the RE in cases from Utah and Lübeck (Germany) indicate a common founder event for some of the patients. In fibroblast and iPS cells, the GGC expansion leads to increased ZFHX3 protein levels, polyG aggregates, and abnormal autophagy, which normalized withZFHX3siRNA. Increasing autophagic flux may provide a therapeutic avenue for this novel polyG disease.

Comment to: “SCA4 Unravelled After More than 25 Years Using Advanced Genomic Technologies”

“…Rudaks et al 1 also cite two other groups for achieving similar findings independently of each other. 3,4 One of those works by Figueroa et al, 3 reported as a manuscript in medRxiv, expanded the clinical descriptions of the original Swedish-American family reported back in 1996 by Flanigan et al 5 However, before all these publications, on October 3, 2023, our group released a manuscript, also in medRxiv, describing three SCA4 families in Sweden, 6 which was not mentioned by Rudaks et al 1 Our group evidently discovered the genetic defect independently of other groups, which illustrates how refined techniques improve diagnostics and contribute to new discoveries. Our group devoted more than a decade working on SCA4, which was part of two theses from the Karolinska Institute.…”