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Updated: Oct 17, 2026
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
Phenotypic study of humanized mice carrying the PAH deep intronic variant c.1199+502A>T
Chuan Zhang1, Yousheng Yan2, Bingbo Zhou1
1Gansu Province Medical Genetics Center, Gansu Provincial Maternity and Child-Care Hospital, Gansu Provincial Central Hospital, Lanzhou, China.
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.
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