title: Altered DNA methylation in PAH deficient phenylketonuria.
abstract: 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.
authors.affiliation: Department of Pathology, Children's Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, United States. Electronic address: dobrowolskis@upmc.edu.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Dobrowolski
authors.affiliation: Genomics and Proteomics Core Laboratories, University of Pittsburgh, 3343 Forbes Avenue, Pittsburgh, PA 15260, United States.
authors.forename: James
authors.initials: J
authors.lastname: Lyons-Weiler
authors.affiliation: Department of Pathology, Children's Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, United States.
authors.forename: Kayla
authors.initials: K
authors.lastname: Spridik
authors.affiliation: Department of Pathology, Children's Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Biery
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, United States.
authors.forename: Jane
authors.initials: J
authors.lastname: Breck
authors.affiliation: Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, 4401 Penn Avenue, Pittsburgh, PA 15224, United States.
authors.forename: Jerry
authors.initials: J
authors.lastname: Vockley
authors.affiliation: Pittsburgh Cytogenetics Laboratory, Magee Women's Hospital, 300 Halket Street, Pittsburgh, PA 15213, United States.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Yatsenko
authors.affiliation: Genomics and Proteomics Core Laboratories, University of Pittsburgh, 3343 Forbes Avenue, Pittsburgh, PA 15260, United States.
authors.forename: Tamanna
authors.initials: T
authors.lastname: Sultana
mesh_terms: D000368:Aged; D001927:Brain Diseases / Q000378:metabolism*; D019175:DNA Methylation; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007962:Leukocytes; D008875:Middle Aged; D010649:Phenylalanine / Q000097:blood; D010651:Phenylalanine Hydroxylase / Q000235:genetics*; D010661:Phenylketonurias / Q000378:metabolism*
chemical_list: D010649:Phenylalanine; D010651:Phenylalanine Hydroxylase
keywords: Biomarker; Gene expression; Methylome; Phenylketonuria