Cep57 organizes pericentriolar material through dual architectural modules and prevents human mosaic variegated aneuploidy

Abstract Mosaic variegated aneuploidy (MVA) is a developmental disorder associated with chromosome segregation defects. Mutations in the centrosomal protein Cep57 cause MVA2 syndrome, yet the molecular basis of Cep57 function has remained unclear. Here, using MINFLUX nanoscopy, structural biology, biochemical approaches, and analyses of patient-derived cells, we show how Cep57 organizes the inner pericentriolar material (PCM) to support centriole biogenesis. We show that Cep57 acts as a molecular bridge between centriolar microtubules and the PCM through two architecturally distinct interactions. Its oligomeric C-terminus anchors to centriolar microtubules, whereas its dimeric N-terminus engages Cep63 through a conserved bundle-like interaction, thereby linking the Cep63–Cep152 platform to the centriole and recruiting Plk4 and other components required for procentriole formation. Analysis of primary T lymphocytes from MVA2 patients carrying the Cep63-binding-defective CEP57 ∆exon 3 mutation reveals a predominant centriole-duplication defect accompanied by minor centriole amplification, likely resulting from disorganized PCM-induced premature centriole disengagement. Our findings show Cep57 as a central architectural organizer that couples centriolar microtubules to the molecular machinery driving centriole biogenesis, providing a mechanistic framework for understanding centrosome dysfunction and aneuploidy-associated diseases.