Distinct pathophysiological mechanisms of CEP152 variants in microcephaly and brain abnormalities

ABSTRACT: Centrosomal protein 152 (CEP152) is essential for centriole function, cell polarity, and neurodevelopment. 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. Cellular analyses revealed centrosome dysfunction, mitotic abnormalities, and increased apoptosis, which were more pronounced in Cep152Q32P/Q32P mice. Electrophysiological and gene expression studies further confirmed variant-specific neuronal impairments, potentially explaining the clinical diversity and severity observed in patients. These findings provide mechanistic insights into how CEP152 variants differently disrupt centrosome function and highlight distinct molecular mechanisms underlying CEP152-related microcephaly and cortical malformations.

ORGANISM(S): Mus musculus

PROVIDER: GSE325064 | GEO | 2026/03/31

REPOSITORIES: GEO