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<p><i>PTEN</i> hamartoma tumor syndrome (PHTS), caused by germline <i>PTEN</i> mutations, exhibits pleiotropic manifestations, including hamartomas, cancers, and neurodevelopmental disorders, posing challenges in patient management. We hypothesized that mutant <i>PTEN</i> allele-dependent alterations during gastrulation impact PHTS pleiotropism. We generated gastruloids from isogenic human induced pluripotent stem cells with clinically relevant heterozygous <i>PTEN</i> mutations, <i>PTEN</i><sup><i>G132D/WT</i></sup> found in PHTS patients with cancer, hamartoma, and autism spectrum disorder, and <i>PTEN</i><sup><i>M134R/WT</i></sup> associated with cancer-only patients. <i>PTEN</i><sup><i>G132D/WT</i></sup>gastruloids exhibited axial over-elongation driven by AKT hyperactivation, upregulation of Snail, a key regulator of epithelial-to-mesenchymal transition (EMT), and enrichments in mesoderm and endoderm-related gene signatures, compared to those with <i>PTEN</i><sup><i>M134R/WT</i></sup> or <i>PTEN</i><sup><i>WT/WT</i></sup>. Our machine-learning algorithm accurately recognized the over-elongated <i>PTEN</i><sup><i>G132D/WT</i></sup> gastruloids and morphological reversal with AKT inhibitor treatment. Our data suggest a potential link between the mutant <i>PTEN</i> allele-specific early developmental alterations and the clinical outcomes of PHTS, and provide a platform for pathogenic mutation and drug screening.</p>

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Pleiotropic germline PTEN mutations influence gastrulation through dysregulated AKT activation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月28日

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  • Omer Enes Onur,
  • Juan Andres Venegas,
  • Arda Durmaz,
  • Shin Chung Kang,
  • Masahiro Hitomi,
  • Charis Eng

摘要

PTEN hamartoma tumor syndrome (PHTS), caused by germline PTEN mutations, exhibits pleiotropic manifestations, including hamartomas, cancers, and neurodevelopmental disorders, posing challenges in patient management. We hypothesized that mutant PTEN allele-dependent alterations during gastrulation impact PHTS pleiotropism. We generated gastruloids from isogenic human induced pluripotent stem cells with clinically relevant heterozygous PTEN mutations, PTENG132D/WT found in PHTS patients with cancer, hamartoma, and autism spectrum disorder, and PTENM134R/WT associated with cancer-only patients. PTENG132D/WTgastruloids exhibited axial over-elongation driven by AKT hyperactivation, upregulation of Snail, a key regulator of epithelial-to-mesenchymal transition (EMT), and enrichments in mesoderm and endoderm-related gene signatures, compared to those with PTENM134R/WT or PTENWT/WT. Our machine-learning algorithm accurately recognized the over-elongated PTENG132D/WT gastruloids and morphological reversal with AKT inhibitor treatment. Our data suggest a potential link between the mutant PTEN allele-specific early developmental alterations and the clinical outcomes of PHTS, and provide a platform for pathogenic mutation and drug screening.