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Background <p>The c.1199 + 502&#xa0;A &gt; T variant of the phenylalanine hydroxylase (<i>PAH</i>) gene, which is the most frequently reported deep intronic variant involved in phenylketonuria (PKU), is mainly observed in patients with classical or mild PKU. Prior to this study, no mouse models of PKU featuring deep intronic variants of <i>PAH</i> had been reported.</p> Methods <p>To phenotypically simulate the pathogenicity of this variant, we used CRISPR/Cas9 genome editing technology and homologous recombination to generate homozygous PKU model mice with a partially humanized <i>Pah</i> gene incorporating human <i>PAH</i> exons 11–12 carrying c.1199 + 502&#xa0;A &gt; T or wild-type (c.1199 + 502WT) control sequences.</p> Results <p>Humanized homozygous <i>Pah</i> c.1199 + 502&#xa0;A &gt; T mice exhibited a classical PKU phenotype, including a higher serum phenylalanine concentration, yellowing of the fur, and other traits. The homozygous mutant group had poorer spatial learning and spatial memory compared with the wild-type group.</p> Conclusion <p>This construction of the first humanized mice carrying a deep intronic variant of <i>PAH</i> provides a new animal model for the pathogenesis and treatment of PKU, and may serve as a reference for future research on the pathogenicity of deep intronic variation.</p>

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Phenotypic study of humanized mice carrying the PAH deep intronic variant c.1199+502A>T

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月26日

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  • Chuan Zhang,
  • Yousheng Yan,
  • Bingbo Zhou,
  • Huimin Gao,
  • Xiaohua Jin,
  • Ling Hui,
  • Shengju Hao,
  • Zongfu Cao,
  • Xu Ma

摘要

Background

The c.1199 + 502 A > T variant of the phenylalanine hydroxylase (PAH) gene, which is the most frequently reported deep intronic variant involved in phenylketonuria (PKU), is mainly observed in patients with classical or mild PKU. Prior to this study, no mouse models of PKU featuring deep intronic variants of PAH had been reported.

Methods

To phenotypically simulate the pathogenicity of this variant, we used CRISPR/Cas9 genome editing technology and homologous recombination to generate homozygous PKU model mice with a partially humanized Pah gene incorporating human PAH exons 11–12 carrying c.1199 + 502 A > T or wild-type (c.1199 + 502WT) control sequences.

Results

Humanized homozygous Pah c.1199 + 502 A > T mice exhibited a classical PKU phenotype, including a higher serum phenylalanine concentration, yellowing of the fur, and other traits. The homozygous mutant group had poorer spatial learning and spatial memory compared with the wild-type group.

Conclusion

This construction of the first humanized mice carrying a deep intronic variant of PAH provides a new animal model for the pathogenesis and treatment of PKU, and may serve as a reference for future research on the pathogenicity of deep intronic variation.