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.
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 PKUmice 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.
Authors: Mara Dierssen; Laura Fedrizzi; Rosa Gomez-Villafuertes; María Martinez de Lagran; Alfonso Gutierrez-Adan; Ignasi Sahún; Belen Pintado; Juan C Oliveros; Xose M Dopazo; Paz Gonzalez; Marisa Brini; Britt Mellström; Ernesto Carafoli; Jose R Naranjo Journal: Front Mol Neurosci Date: 2012-05-03 Impact factor: 5.639