Altered brain gene expression profiles associated with the pathogenesis of phenylketonuria in a mouse model

作者：Park Joo Won; Park Eun Sook; Choi Eun Nam; Park Hae Young; Jung Sung Chul^*

来源：Clinica Chimica Acta, 2009, 401(1-2): 90-99.

DOI：10.1016/j.cca.2008.11.019

• Phenylketonuria
• Mouse
• Brain
• Biomarker
• Transthyretin
• Klotho

Background: Phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of phenylalanine hydroxylase (PAH), which catalyzes the conversion of phenylalanine to tyrosine. The resultant hyperphenylalaninemia causes mental retardation, seizure, and abnormalities in behavior and movement.
Methods: We analyzed gene expression profiles in brain tissues of Pah(enu2) mice to elucidate the mechanisms involved in phenylalanine-induced neurological damage. The altered gene expression was confirmed by real-time PCR and Western blotting. To identify markers associated with neurological damage, we examined TTR expression in serum by Western blotting.
Results: Gene expression profiling of brain tissue from a mouse model of PKU revealed overexpression of transthyretin (Ttr), sclerostin domain containing 1 (Sostdc1), alpha-Klotho (Kl), prolactin receptor (Prlr), and early growth response 2 (Egr2). In contrast to its overexpression in the brain, TTR expression was low in the sera of PKU mice offered unrestricted access to a diet containing phenylalanine. Expression of TTR decreased in a time-dependent manner in phenylalanine-treated HepG2 cells.
Conclusions: These findings indicate that Ttr, Sostdc1, Kl, Prlr, and Egr2 can be involved in the pathogenesis of PKU and that phenylalanine might have a direct effect on the level of TTR in serum.

• 出版日期2009-3