Distinct pathophysiological mechanisms of CEP152 variants in microcephaly and brain abnormalities
Nanako Hamada1, Lama AlAbdi2, Tomoko Uehara3,4
1Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability Center, Kasugai, 480-0392, Japan.
EMBO Molecular Medicine
|May 5, 2026
Summary
Distinct CEP152 gene variants cause microcephaly through different mechanisms, impacting neurodevelopment and brain structure differently. Understanding these variant effects clarifies the spectrum of microcephaly severity.
Area of Science:
- Genetics
- Neuroscience
- Cell Biology
Background:
- CEP152 is crucial for centriole function and neurodevelopment.
- Pathogenic recessive CEP152 variants are linked to primary microcephaly.
- Microcephaly presents a spectrum of severity and associated brain abnormalities.
Purpose of the Study:
- To investigate the functional impact of novel and known CEP152 variants.
- To elucidate the distinct molecular and cellular mechanisms underlying CEP152-related microcephaly.
- To correlate genotype with phenotype severity in microcephaly patients and mouse models.
Main Methods:
- Identification and analysis of compound heterozygous and homozygous CEP152 variants.
- In vitro assays to assess protein localization, degradation, and kinase interactions.
- In vivo studies using Cep152 knock-in mouse models.
- Cellular, morphological, electrophysiological, and gene expression analyses.
Main Results:
- Novel compound heterozygous variants (p.W105* and p.K897*) and a homozygous variant (p.Q32P) were identified in microcephalic patients.
- p.K897* abolished centrosomal localization; p.W105* caused protein degradation; p.Q32P disrupted Polo-like kinase 4 binding.
- Both mouse models (Cep152W105*/K897* and Cep152Q32P/Q32P) exhibited microcephaly, with Cep152Q32P/Q32P showing severe cortical defects.
- Cep152Q32P/Q32P brains displayed exacerbated centrosome dysfunction, mitotic errors, apoptosis, and structural abnormalities.
Conclusions:
- Distinct CEP152 variants impair neurodevelopment via different molecular mechanisms.
- These mechanisms explain the varying severity and phenotypes observed in microcephaly.
- The study highlights the critical role of CEP152 in normal brain development and centriole function.
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