KBG syndrome-associated protein ANKRD11 regulates SETD5 expression to modulate rRNA levels and translation.

ANKRD11 haploinsufficiency is implicated in KBG syndrome, characterized by intellectual disability, autism spectrum disorders, and skeletal abnormalities. While SETD5 mutations are linked to a distinct clinical disorder, they also appear in KBG-like cases, suggesting shared molecular pathways. Here, we show that ANKRD11-deficient neural cells exhibit reduced ribosomal RNA (rRNA) and translation. Although ANKRD11 primarily localizes outside the nucleolus, where rDNA transcription occurs, it indirectly promotes rRNA expression by upregulating SETD5, a transcriptional activator of rRNA. Mechanistically, ANKRD11 interacts with the Setd5 promoter and recruits WDR5, a component of the histone H3 lysine 4 (H3K4) methyltransferase complex involved in transcriptional activation. Correspondingly, reduced H3K4 methylation on the Setd5 promoter correlates with diminished SETD5 expression in ANKRD11-deficient cells. Overexpression of ANKRD11 or SETD5 restores rRNA levels and translational activity. These findings underscore the role of the ANKRD11-SETD5 axis in alleviating KBG syndrome pathogenesis, offering insights into potential therapeutic targets.