Distinct pathophysiological mechanisms of CEP152 variants in microcephaly and brain abnormalities

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Abstract
CEP152 is essential for centriole function and neurodevelopment, and pathogenic recessive variants in CEP152 cause primary microcephaly. We identified new compound heterozygous CEP152 variants, c.314 G > A,p.(W105*) and c.2689 A > T,p.(K897*), in a microcephalic patient and analyzed them alongside a homozygous variant c.95 A > C,p.(Q32P) associated with severe microcephaly with marked gyral simplification. In vitro assays revealed distinct effects: p.K897* prevented centrosomal localization, p.W105* led to protein degradation, and p.Q32P retained centrosomal targeting but disrupted binding to Polo-like kinase 4, a key centriole biogenesis kinase and CEP152 partner. In vivo, both Cep152 W105*/K897* and Cep152 Q32P/Q32P knock-in mice displayed microcephaly; notably, Cep152 Q32P/Q32P mice also exhibited severe cortical defects during brain development. Cellular analyses revealed centrosome dysfunction, mitotic errors, and increased apoptosis, which were exacerbated in Cep152 Q32P/Q32P brains. Morphological examination, including electron microscopy, further demonstrated structural abnormalities of the centrosomes and centrioles in Cep152 Q32P/Q32P brains. Electrophysiological and gene expression analyses confirmed variant-specific neuronal impairments, which correlate with clinical severity. Collectively, these findings demonstrate that distinct CEP152 variants disrupt neurodevelopment through different mechanisms, thereby explaining the spectrum of microcephaly severity and associated phenotypes.
Funding Information
  • Japan Society for the Promotion of Science (JP22H03049)
  • Japan Society for the Promotion of Science (JP20K21589)
  • Japan Society for the Promotion of Science (23K07284)
  • Japan Society for the Promotion of Science (JP22H04926)
  • Daiko Foundation (9234)
  • Israel Science Foundation (1863/24)

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