What question did this study set out to answer?

To characterize novel genetic variations in the PAH gene associated with phenylketonuria in Chinese patients.

April 12, 2026Open Access

Genetic diagnosis and molecular characterization of three novel variations in the phenylalanine hydroxylase gene from Chinese patients with phenylketonuria

Key Points

To characterize novel genetic variations in the PAH gene associated with phenylketonuria in Chinese patients.
Analyzed genetic variations in three novel PAH gene mutations in affected families.
Performed qRT-PCR to assess transcript levels of PAH variants.
Used immunoblotting to evaluate protein levels of PAH variants.
Measured enzyme activity of identified PAH mutants compared to wild type.
Identified three novel variants in the PAH gene, including one missense and two deletions.
PAH variants resulted in significantly reduced enzyme activity compared to controls (P < 0.001).
Two deletions were determined to be clinically significant for PKU pathogenesis.

Abstract

Loss-of-function variants in the human phenylalanine hydroxylase (PAH) gene are the most common genetic causal factors for Phenylketonuria (PKU). Currently, a broad spectrum of variations is recognized in the human PAH gene. However, the molecular function and clinical significance of some novel PAH variants remain unclear. Here, we report on five PKU-affected families carrying three novel PAH variants, including one missense variant (PAH: c. 271C>A (p. Leu91Met) ) and two deletions (PAH: c. 206₂08delCTT (p. Ser70del) and PAH: c. 541₅44delGAGG (p. Glu181Lysfs*13) ). These variations constitute different compound heterozygous genotypes with other known pathogenic variants such as PAH: c. 721C>T (p. Arg241Cys), PAH: c. 168+5G>C, and PAH: c. 1238G>C (p. Arg413Pro), which probably led to the patients’ PKU etiopathology. qRT-PCR and immunoblotting showed that the protein levels of PAH (S70del) and PAH (E181Kfs*13) were significantly reduced compared with the wild-type control, although their transcript levels were not. Also, the enzyme activity of PAH (S70del) and PAH (E181Kfs*13) mutants was significantly decreased relative to the wild type (P A (p. Leu91Met) had no significant effect on PAH mRNA and protein levels or enzyme activity. Collectively, our data demonstrate that the two deletions PAH: c. 206₂08delCTT and PAH: c. 541₅44delGAGG are clinically significant for pathogenicity. Our findings are anticipated to contribute to the advancement of prenatal diagnosis, population-based carrier screening, and genetic counseling for individuals affected by PKU, and is expected to help reduce the incidence of PKU and ameliorate the associated disease burden.

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Cite This Study

Yang et al. (Tue,) studied this question.

synapsesocial.com/papers/69db37404fe01fead37c53aa https://doi.org/https://doi.org/10.17179/excli2026-9271

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