Reversal of gene expression profile in the phenylketonuria mouse model after adeno-associated virus vector-mediated gene therapy

Hyun Jeong Oh, Hyejin Lee, Joo Won Park, Hwanseok Rhee, Soo Kyung Koo, Seongman Kang, Inho Jo, Sung Chul Jung

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10 Scopus citations


Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by phenylalanine hydroxylase (PAH) deficiency. Accumulation of phenylalanine leads to severe mental and psychomotor retardation, and hypopigmentation of skin and hair. We have demonstrated the cognitive outcome of biochemical and phenotypic reversal by the adeno-associated virus vector-mediated gene delivery of a human PAH transgene. In this study, we identified the expression of genes related to pathologic abnormalities of the PKU-affected brain, in which the symptoms of PKU are mainly manifest, and transcriptional changes in effective gene therapy treatment using oligonucleotide array. Therapeutic effectiveness was verified by change in enzyme activity (15 ± 5.84%), phenylalanine plasma level (261 ± 108 μM), and coat color. Our data indicated that 12 genes were significantly up-regulated in PKU. Four are involved in defense and inflammatory responses of neutrophils (NE, MPO, NGP, and CRAMP), three other overexpressed genes are related to extracellular matrix organization and degradation (COL1A1, COL1A2, and MMP13); the remainder were a nociceptor in sensory neurons (MrgA1), a structural gene of P lysozyme (Lzp-s), an immunoglobulin α heavy chain constant region gene (Igh-2), an osteocalcin-related protein precursor (Bglap-rs1), and a membrane-spanning 4 domain, subfamily A, member 3 (Ms4a3). Data demonstrated that elevated genes in the PKU-affected brain could be normalized by human PAH gene delivery. Although we could not precisely link transcript level changes and neurologic pathogenesis, this study provides a more comprehensive understanding of the PKU-affected brain at the molecular level, possibly resulting in better therapeutic approaches.

Original languageEnglish
Pages (from-to)124-132
Number of pages9
JournalMolecular Genetics and Metabolism
Issue numberSUPPL.
StatePublished - Dec 2005

Bibliographical note

Funding Information:
This study was supported by a grant of the Korea 21 R&D Project (01-PJ10-PG6-01GN15-0001), from the Ministry of Health and Welfare, Republic of Korea.


  • Adeno-associated virus
  • Gene therapy
  • Microarray
  • Mouse
  • Neurological pathogenesis
  • Phenylketonuria


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