Relationship between genotype, phenylalanine hydroxylase expression and in vitro activity and metabolic phenotype in phenylketonuria.
Mol Genet Metab
; 125(1-2): 86-95, 2018 09.
Article
em En
| MEDLINE
| ID: mdl-30037505
ABSTRACT
Residual phenylalanine hydroxylase (PAH) activity is the main determinant of the metabolic phenotype in phenylketonuria (PKU). The genotypic heterogeneity of PKU, involving >1000 PAH variants and over 2500 different genotypes, makes genotype-based phenotype prediction challenging. While a relationship between PAH variants and the metabolic phenotype is well established, we questioned the importance of PAH expression and residual in vitro activity for the metabolic phenotype. Thirty-four PAH variants (p.F39â¯L, p.A47V, p.D59Y, p.I65S, p.R68G, p.R68S, p.E76G, p.A104D, p.D143G, p.R155H, p.R176L, p.V190A, p.G218â¯V, p.R241C, p.R243Q, p.P244L, p.R252W, p.R261Q, p.E280K, p.R297H, p.A300S, p.I306V, p.A309V, p.L311P, p.A313T, p.L348â¯V, p.V388â¯M, A403V, p.R408Q, p.R408W, p.R413P, p.D415N, p.Y417H, and p.A434D) were transiently transfected into COS-7 cells, and expression of PAH was investigated. Expression patterns were compared with in vitro PAH activity and allelic phenotype values (APVs). In vitro PAH activity was significantly higher (pâ¯<â¯.01) in variants associated with mild hyperphenylalaninemia (PAH activityâ¯=â¯52.1⯱â¯8.5%; APVâ¯=â¯6.7-10.0) than that in classic PKU variants (PAH activityâ¯=â¯21.1⯱â¯7.0%; APVâ¯=â¯0-2.7). Mild PKU variants (PAH activityâ¯=â¯40.2⯱â¯7.6%; APVâ¯=â¯2.8-6.6) were not significantly different from mild hyperphenylalaninemia, but there was a difference (pâ¯<â¯.048) compared with classic PKU phenotypes.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fenilalanina Hidroxilase
/
Fenilcetonúrias
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Heterogeneidade Genética
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article