DNA methylation in the pathophysiology of hyperphenylalaninemia in the PAH(enu2) mouse model of phenylketonuria

Molecular Genetics and Metabolism
S F DobrowolskiA Biery

Abstract

Phenylalanine hydroxylase deficient phenylketonuria (PKU) is the paradigm for a treatable inborn error of metabolism where maintaining plasma phenylalanine (Phe) in the therapeutic range relates to improved clinical outcomes. While Phe is the presumed intoxicating analyte causal in neurologic damage, the mechanism(s) of Phe toxicity has remained elusive. Altered DNA methylation is a recognized response associated with exposure to numerous small molecule toxic agents. Paralleling this effect, we hypothesized that chronic Phe over-exposure in the brain would lead to aberrant DNA methylation with secondary influence upon gene regulation that would ultimately contribute to PKU neuropathology. The PAH(enu2) mouse models human PKU with intrinsic hyperphenylalaninemia, abnormal response to Phe challenge, and neurologic deficit. To examine this hypothesis, we assessed DNA methylation patterns in brain tissues using methylated DNA immunoprecipitation and paired end sequencing in adult PAH(enu2) animals maintained under either continuous dietary Phe restriction or chronic hyperphenylalaninemia. Heterozygous PAH(enu2/WT) litter mates served as controls for normal Phe exposure. Extensive repatterning of DNA methylation was observed in brai...Continue Reading

Citations

Mar 7, 2020·Journal of Neuroscience Research·Bruna Klippel FerreiraPatricia Fernanda Schuck
Feb 20, 2021·Molecular Genetics and Metabolism·Steven F DobrowolskiHarry C Blair
May 22, 2021·Nature Reviews. Disease Primers·Francjan J van SpronsenAnnet M Bosch
Aug 26, 2021·Organogenesis·Steven F DobrowolskiHarry C Blair

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