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<p>Genome-wide association studies report single nucleotide polymorphisms (SNPs) in the <i>PKHD1-TFAP2B</i> genomic interval are associated with primary open-angle glaucoma (POAG) but do not distinguish the causal gene. While neural crest cell (NCC)-specific <i>Tfap2b</i> inactivation causes anterior segment dysgenesis (ASD) and congenital glaucoma (CG), <i>PKHD1</i> mutations cause autosomal recessive polycystic kidney disease. We now show that <i>Pkhd1</i><sup><i>del3-67/del3-67</i></sup> mice also exhibit CG and ASD. Integrating genetic, epigenetic, bioinformatic and developmental analyses, we show that <i>Pkhd1</i><sup><i>del3-67/del3-67</i></sup> mice lack <i>Tfap2b</i> and AP-2β expression in a subset of periocular mesenchymal cells at E13.5 and its derivatives. Our data suggest the <i>Pkhd1</i><sup><i>del3-67</i></sup> deletion disrupts features of the <i>Pkhd1-Tfap2b</i> genomic architecture essential for <i>Tfap2b</i> cell-specific function. Consistent with this model, <i>Pkhd1</i><sup><i>del3-67/+</i></sup><i>;Tfap2b</i><sup><i>ko/+</i></sup>mice develop ASD and lack <i>Tfap2b</i> and AP-2β in relevant cell-types. Our results suggest POAG-associated SNPs at this complex locus may impact disease risk by altering <i>TFAP2B</i> regulatory landscapes, providing a mechanistic link and highlighting regulatory complexity of disease-associated regions.</p>

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Deletion of ARPKD-associated Pkhd1 gene in mice results in decreased Tfap2b expression and eye abnormalities

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月23日

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  • Yu Ishimoto,
  • Luis F. Menezes,
  • Naoki Nakaya,
  • Karla Barbosa-Sabanero,
  • Yukihiro Horie,
  • Teruhiko Yoshida,
  • Jeff M. Reece,
  • Fang Zhou,
  • Stanislav Tomarev,
  • Laura Kerosuo,
  • Gregory G. Germino

摘要

Genome-wide association studies report single nucleotide polymorphisms (SNPs) in the PKHD1-TFAP2B genomic interval are associated with primary open-angle glaucoma (POAG) but do not distinguish the causal gene. While neural crest cell (NCC)-specific Tfap2b inactivation causes anterior segment dysgenesis (ASD) and congenital glaucoma (CG), PKHD1 mutations cause autosomal recessive polycystic kidney disease. We now show that Pkhd1del3-67/del3-67 mice also exhibit CG and ASD. Integrating genetic, epigenetic, bioinformatic and developmental analyses, we show that Pkhd1del3-67/del3-67 mice lack Tfap2b and AP-2β expression in a subset of periocular mesenchymal cells at E13.5 and its derivatives. Our data suggest the Pkhd1del3-67 deletion disrupts features of the Pkhd1-Tfap2b genomic architecture essential for Tfap2b cell-specific function. Consistent with this model, Pkhd1del3-67/+;Tfap2bko/+mice develop ASD and lack Tfap2b and AP-2β in relevant cell-types. Our results suggest POAG-associated SNPs at this complex locus may impact disease risk by altering TFAP2B regulatory landscapes, providing a mechanistic link and highlighting regulatory complexity of disease-associated regions.