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Structural and functional analyses of mutations of the human phenylalanine hydroxylase gene, Clin Ch…

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작성자 관리자 작성일2016-06-15 조회19,003회


Structural and functional analyses of mutations of the human phenylalanine hydroxylase gene,

 Kim SWJung JOh HJKim JLee KSLee DHPark CKimm KKoo SKJung SC.  †First authors.



Phenylketonuria (PKU) is an inborn error of metabolism that results from a deficiency of phenylalanine hydroxylase (PAH). We demonstrated PAH mutational spectrum from patients with PKU, including 10 novel and 3 tetrahydrobiopterin (BH(4))-responsive mutations. In this study, 11 PAH missense mutations, including 6 novel mutations (P69S, G103S, L293M, G332V, S391I, A447P) found in our previous study, 2 mutations common in east Asian patients with PKU (R243Q, R413P), and 3 tetrahydrobiopterin (BH(4))-responsive mutations (R53H, R241C, R408Q) have been functionally and structurally analyzed.

A transient protein overexpression system and an in vitro BH(4)-responsiveness study were used. The effects of PAH missense mutations on the PAH protein structure were also analyzed. To determine the conservation of 12 mutated residues, PAH was aligned using BLAST against full genomic sequences of 221 different species. Model structures of PAH protein and the composite tetramer were constructed using the software program, SHEBA.

No PAH activity was detected for some mutants. However, the residual activities associated with other mutants ranged over a wide spectrum. The missense mutations responsive to BH(4) were not highly conserved throughout the 43 species in the multiple sequence alignment that encode PAH. The composite model structure of PAH revealed that dimer stability was reduced in the BH(4)-responsive mutants, whereas tetramer stability remained normal.

This expression study analyzed PAH mutations and model structures of mutant PAH proteins are proposed. Correlation between the proposed mutant PAH structures and functions are suggested.

[PubMed - indexed for MEDLINE]

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