GGC expansion inZFHX3causes SCA4 and impairs autophagy

Abstract

AbstractDespite 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.