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Background <p>Biallelic <i>DIAPH1</i> 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.</p> Methods <p>Whole exome sequencing was performed on a patient’s peripheral blood to identify <i>DIAPH1</i> mutations. A zebrafish model was established by microinjecting mutant human <i>DIAPH1</i> cDNA into one-cell embryos (no zebrafish <i>DIAPH1</i> 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 (<i>P</i> &lt; 0.05, <i>P</i> &lt; 0.0001 for significance).</p> Results <p>Compound heterozygous <i>DIAPH1</i> mutations (c.1051&#xa0;C &gt; T, p.R351X; c.609delA, p.E203E fs*19) were found and associated with clinical symptoms. Mutant <i>DIAPH1</i> zebrafish showed abnormal eye shape, shortened body length, axis defects, impaired motor axon growth, reduced locomotor activity, upregulated <i>WNT8A</i>, <i>WNT9A</i>, <i>LRP5</i>, <i>LRP6</i>, and downregulated <i>AXIN1</i>, <i>AXIN2</i>, <i>β-CATENIN</i>, indicating excessive Wnt/β-catenin pathway activation.</p> Conclusions <p><i>DIAPH1</i> 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 <i>DIAPH1</i>-related microcephaly, advancing understanding of hereditary primary microcephaly pathogenesis and potential therapeutic target exploration.</p>

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DIAPH1 regulates the Wnt/β-catenin pathway resulting in microcephaly and visual impairment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月10日

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  • Dayan Wang,
  • Panjian Lai,
  • Kan Wang,
  • Zhuanbin Wu,
  • Xiaobing Li

摘要

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.