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

Authors

  • Fan Yang No. 69, Beihuan Road, Liandu District, Lishui Key Laboratory of Brain Health and Severe Brain Disorders, Lishui Second People’s Hospital, Wenzhou Medical University, Lishui, 323000, Zhejiang Province, China. E-mail: yangfan@sibs.ac.cn https://orcid.org/0000-0002-1659-956X
  • Hua-Feng Li Department of Medical Genetics, Women & Children’s Health Care Hospital of Linyi, Linyi, China https://orcid.org/0000-0002-6751-2671
  • Wei-Jia Tang The Research Center for Lin He Academician New Medicine, Institutes for Shanghai Pudong Decoding Life, Shanghai, China https://orcid.org/0009-0003-8797-7630
  • Jin-Ping Zhu Department of Medical Genetics, Women & Children’s Health Care Hospital of Linyi, Linyi, China https://orcid.org/0000-0003-4871-2034
  • Ji-Gang Qiu Department of Medical Genetics, Women & Children’s Health Care Hospital of Linyi, Linyi, China https://orcid.org/0000-0002-5105-9294
  • Tian-E. Cai Medical Genetics & Antenatal Diagnosis Center, Hainan Branch, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Sanya, China https://orcid.org/0009-0006-0598-0134
  • Li-Mei Yu Key Laboratory of Cell Engineering in Guizhou Province, Affiliated Hospital of Zunyi Medical University, Zunyi, China https://orcid.org/0000-0002-3377-1202
  • Ying Yu Medical Genetics & Antenatal Diagnosis Center, Hainan Branch, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Sanya, China No. 339, Yingbin Road, Jiyang District, Sanya City, 572022, Hainan Province, China. E-mail: yuying2020@126.com https://orcid.org/0009-0007-5632-6201

DOI:

https://doi.org/10.17179/excli2026-9271

Keywords:

phenylketonuria, hyperphenylalaninemia, phenylalanine hydroxylase, novel deletion, pathogenic variation, mRNA and protein expression, enzyme activity

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.206_208delCTT (p.Ser70del) and PAH: c.541_544delGAGG (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 < 0.001). PAH: c.271C>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.206_208delCTT and PAH: c.541_544delGAGG 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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Published

2026-04-10

How to Cite

Yang, F., Li, H.-F., Tang, W.-J., Zhu, J.-P., Qiu, J.-G., Cai, T.-E., … Yu, Y. (2026). Genetic diagnosis and molecular characterization of three novel variations in the phenylalanine hydroxylase gene from Chinese patients with phenylketonuria. EXCLI Journal, 25, 458–475. https://doi.org/10.17179/excli2026-9271

Issue

Vol. 25 (2026)

Section

Original articles

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Copyright (c) 2026 Fan Yang, Hua-Feng Li, Wei-Jia Tang, Jin-Ping Zhu, Ji-Gang Qiu, Tian-E. Cai, Li-Mei Yu, Ying Yu

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