Distinct pathophysiological mechanisms of CEP152 variants in microcephaly and brain abnormalities

Pathogenic variants in CEP152 cause autosomal recessive primary microcephaly 9 (MCPH9), though the underlying mechanisms remain poorly understood. Here, we identified novel compound heterozygous variants, c.314G>A,p.(W105*) and c.2689A>T,p.(K897*) in a patient with microcephaly, and analyzed them alongside a homozygous variant, c.95A>C,p.(Q32P), which is associated with atypically severe brain malformations in addition to microcephaly.

Functional assays revealed distinct variant-specific effects: p.K897* disrupted centrosomal localization, p.W105* led to protein degradation, and p.Q32P retained centrosomal localization but impaired interaction with Polo-like kinase 4, a CEP152 partner and a microcephaly-causative protein. To assess pathogenicity in vivo, we generated Cep152W105*/K897* and Cep152 18 Q32P/Q32P mouse models. Both exhibited microcephaly with reduced body weight, but Cep152 19 Q32P/Q32P mice additionally displayed severe brain malformations, including ventricular dilation and neuronal mispositioning.