BMC Med Genomics. 2026 Apr 10. doi: 10.1186/s12920-026-02364-z. Online ahead of print.
ABSTRACT
BACKGROUND: Biallelic DIAPH1 mutations are linked to hereditary microcephaly syndrome, yet the underlying pathogenic mechanism remains unelucidated. This study aimed to clarify how DIAPH1 biallelic mutations cause microcephaly and visual impairment, focusing on the gene’s regulatory role in the Wnt/β-catenin signaling pathway.
METHODS: Whole exome sequencing was performed on a patient’s peripheral blood to identify DIAPH1 mutations. A zebrafish model was established by microinjecting mutant human DIAPH1 cDNA into one-cell embryos (no zebrafish DIAPH1 homolog exists). Phenotypic analyses (morphology, neuronal axon growth, behavior) and quantitative real-time PCR for Wnt/β-catenin pathway genes were conducted. Data were mean ± SEM; statistical tests (Student’s t-test, ANOVA, χ²) used GraphPad Prism 5.0 (P < 0.05, P < 0.0001 for significance).
RESULTS: Compound heterozygous DIAPH1 mutations (c.1051 C > T, p.R351X; c.609delA, p.E203E fs*19) were found and associated with clinical symptoms. Mutant DIAPH1 zebrafish showed abnormal eye shape, shortened body length, axis defects, impaired motor axon growth, reduced locomotor activity, upregulated WNT8A, WNT9A, LRP5, LRP6, and downregulated AXIN1, AXIN2, β-CATENIN, indicating excessive Wnt/β-catenin pathway activation.
CONCLUSIONS: DIAPH1 compound heterozygous mutations may trigger microcephaly and visual impairment by abnormally activating the Wnt/β-catenin pathway. The zebrafish model provides a reliable in vivo system for studying DIAPH1-related microcephaly, advancing understanding of hereditary primary microcephaly pathogenesis and potential therapeutic target exploration.
PMID:41963888 | DOI:10.1186/s12920-026-02364-z
