Influence of the WDR4 c.251G>A (p.R84H) variant on the transcriptome in human fibroblasts

The WD repeat-containing protein 4 (WDR4) has repeatedly been associated with primary microcephaly, a condition of impaired brain and skull growth, which may be due to faulty cilia. Here, we show using a combination of approaches in human fibroblasts, zebrafish embryos and patient-derived cells that WDR4 facilitates cilium formation. Molecularly, we associated WDR4 loss-of-function with increased protein synthesis and concomitant upregulation of proteasomal activity, while ubiquitin precursor pools are reduced. Inhibition of proteasomal activity as well as supplementation with free ubiquitin restored normal ciliogenesis. Proteasome inhibition ameliorated microcephaly phenotypes. Thus, we propose that WDR4 loss-of-function impairs head growth and neurogenesis via aberrant cilia formation, initially caused by disturbed protein and ubiquitin homeostasis. RNA sequencing of human fibroblast cell line samples: 8 samples: 4 control samples (1BR3) and 4 WDR4-R84H samples Submitter states that missing raw files are due to patient privacy concerns for the 4 WDR4-R84H samples.