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Alterations in protein aggregation and degradation due to mild and severe missense mutations (A104D, R157N) in the human phenylalanine hydroxylase gene (PAH)

Phenylalanine hydroxylase (PAH) catalyzes the conversion of phenylalanine to tyrosine; its activity is the major determinant of phenylalanine disposal. Mutations in the corresponding human gene (PAH), which encodes the human hepatic PAH enzyme, result in hyperphenylalaninemia; the resulting phenotypes can range in severity from mild forms of hyperphenylalaninemia with benign outcome to the severe form, phenylketonuria with impaired cognitive development. This paper describes the detailed characterization of two inherited recessive missense mutations in PAH, c.311C→A (A104D) and [c.470G→A;c.471A→C] (R157N), which are associated, respectively, in the homozygous or functionally hemizygous states, with mild and severe metabolic phenotypes. We used three different in vitro PAH expression systems (in Escherichia coli, cell‐free rabbit reticulocyte lysates, and human embryonal kidney cells), as well as a unique assay for phenylalanine oxidation in vivo. In each system, we observed alterations of PAH function and physical properties, compared with wild‐type enzyme, and differences in relative severity of effects between these two mutations. Pulse‐chase experiments showed increased PAH degradation, probably related to observed aberrations in protein folding and altered oligomerization, as a basic mechanism underlying effects of these missense mutations. Hum Mutat 12:344–354, 1998.© 1998 Wiley‐Liss, Inc.