Altered brain gene expression profiles associated with the pathogenesis of phenylketonuria in a mouse model.
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.
Park
Joo-Won
JW
Department of Biochemistry, School of Medicine, Ewha Womans University, Seoul, South Korea.
Park
Eun-Sook
ES
Choi
Eun Nam
EN
Park
Hae-Young
HY
Jung
Sung-Chul
SC
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics; D001921:Brain / Q000378:metabolism*; D002460:Cell Line; D004195:Disease Models, Animal; D051767:Early Growth Response Protein 2 / Q000235:genetics; D020869:Gene Expression Profiling; D005966:Glucuronidase / Q000235:genetics; D000090265:Klotho Proteins; D051379:Mice; D010661:Phenylketonurias / Q000235:genetics*; D011228:Prealbumin / Q000235:genetics; D011981:Receptors, Prolactin / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D051767:Early Growth Response Protein 2; C497327:Egr2 protein, mouse; D011228:Prealbumin; D011981:Receptors, Prolactin; C483887:Sostdc1 protein, mouse; D005966:Glucuronidase; D000090265:Klotho Proteins