Mutational spectrum of the phenylalanine hydroxylase gene in patients with phenylketonuria in the central region of China

Abstract

Phenylketonuria (PKU, OMIM 261600) caused by phenylalanine hydroxylase (PAH) deficiency is an autosomal recessive disease that is characterized by abnormalities of phenylalanine metabolism. In this study, a total of 77 patients, originating from the central region of China and who were diagnosed with PAH deficiency at the third affiliated hospital of Zhengzhou University, were enrolled in this study. The 13 exons and 12 flanking introns of the PAH gene were analyzed by Sanger sequencing and next generation sequencing. The sequencing data were aligned to the hg19, PAHvdb and HGMD databases to characterize the genotypes of PKU patients, and genotype–phenotype correlations and BH4 responsiveness predictions were performed using BIOPKUdb. In total, 149 alleles were characterized among the 154 PKU alleles. These mutations were located in exons 2–13, and intron 12 of the PAH gene, with a relative frequency of ≥5%, for EX6-96A>G, p.R241C, p.R243Q, p.V399V and p.R53H. Additionally, a novel variant, p.D84G, was identified. The genotype correlated with clinical symptoms in 33.3–100% of the cases, depending on the disease severity, and BH4 responsiveness predictions show that only five patients with MHP-PKU and one patient with Mild-PKU were predicted to be BH4 responsive. In conclusion, we have characterized the mutational spectrum of PAH in the central region of China and have identified a novel mutation. The hotspot mutation information might be useful for screening, diagnosis and treatment of PKU.

Keywords:

• Phenylketonuria (PKU)
• phenylalanine hydroxylase (PAH)
• gene mutation frequency
• mutational spectrum
• PAH deficiency
• genotypes
• novel variants
• tetrahydrobiopterin (BH4)
• Sanger sequencing
• next generation sequencing

Acknowledgements

The authors would like to thank Liting Jia for her great help in specimen collection.

Compliance with ethical standards: This study was approved by the Institutional Review Board of the Third Affiliated Hospital of Zhengzhou University. Written informed consent was obtained from all participants and, if younger than 18 years, their parents/guardians.

Geolocation information: The geolocation information from Google map is N34°44′36.12″, E113°38′53.03″.

Disclosure statement

The authors declare that they have no competing interests.

Additional information

Funding

This work was supported by the Foundation Program of the Henan Province Technical Collaborative Projects under Grant number 142106000044 and Foundation Program of the Shangqiu City Technical Collaborative Projects.