Altered DNA methylation in PAH deficient phenylketonuria

Mol Genet Metab. 2015 Jun-Jul;115(2-3):72-7. doi: 10.1016/j.ymgme.2015.04.002. Epub 2015 Apr 24.


While phenylalanine (PHE) is the toxic insult in phenylketonuria (PKU), mechanisms underlying PHE toxicity remain ill-defined. Altered DNA methylation in response to toxic exposures is well-recognized. DNA methylation patterns were assessed in blood and brain from PKU patients to determine if PHE toxicity impacts methylation. Methylome assessment, utilizing methylated DNA immunoprecipitation and paired-end sequencing, was performed in DNA obtained from brain tissue of classical PKU patients, leukocytes from poorly controlled PKU patients, leukocytes from well controlled PKU patients, and appropriate control tissues. In PKU brain tissue, expression analysis determined the impact of methylation on gene function. Differential methylation was observed in brain tissue of PKU patients and expression studies identified downstream impact on gene expression. Altered patterns of methylation were observed in leukocytes of well controlled and poorly controlled patients with more extensive methylation in patients with high PHE exposure. Differential methylation of noncoding RNA genes was extensive in patients with high PHE exposure but minimal in well controlled patients. Methylome repatterning leading to altered gene expression was present in brain tissue of PKU patients, suggesting a role in neuropathology. Aberrant methylation is observed in leukocytes of PKU patients and is influenced by PHE exposure. DNA methylation may provide a biomarker relating to historic PHE exposure.

Keywords: Biomarker; Gene expression; Methylome; Phenylketonuria.

MeSH terms

  • Aged
  • Brain Diseases / metabolism*
  • DNA Methylation*
  • Female
  • Frontal Lobe / metabolism
  • Frontal Lobe / pathology
  • Humans
  • Leukocytes
  • Middle Aged
  • Phenylalanine / blood
  • Phenylalanine Hydroxylase / genetics*
  • Phenylketonurias / metabolism*


  • Phenylalanine
  • Phenylalanine Hydroxylase