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Relationship between genotype, phenylalanine hydroxylase expression and in vitro activity and metabolic phenotype in phenylketonuria


Himmelreich, Nastassja; Shen, Nan; Okun, Jürgen G; Thiel, Christian; Hoffmann, Georg F; Blau, Nenad (2018). Relationship between genotype, phenylalanine hydroxylase expression and in vitro activity and metabolic phenotype in phenylketonuria. Molecular Genetics and Metabolism, 125(1-2):86-95.

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.F39 L, p.A47V, p.D59Y, p.I65S, p.R68G, p.R68S, p.E76G, p.A104D, p.D143G, p.R155H, p.R176L, p.V190A, p.G218 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.L348 V, p.V388 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 (p < .01) in variants associated with mild hyperphenylalaninemia (PAH activity = 52.1 ± 8.5%; APV = 6.7–10.0) than that in classic PKU variants (PAH activity = 21.1 ± 7.0%; APV = 0–2.7). Mild PKU variants (PAH activity = 40.2 ± 7.6%; APV = 2.8–6.6) were not significantly different from mild hyperphenylalaninemia, but there was a difference (p < .048) compared with classic PKU phenotypes.

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.F39 L, p.A47V, p.D59Y, p.I65S, p.R68G, p.R68S, p.E76G, p.A104D, p.D143G, p.R155H, p.R176L, p.V190A, p.G218 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.L348 V, p.V388 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 (p < .01) in variants associated with mild hyperphenylalaninemia (PAH activity = 52.1 ± 8.5%; APV = 6.7–10.0) than that in classic PKU variants (PAH activity = 21.1 ± 7.0%; APV = 0–2.7). Mild PKU variants (PAH activity = 40.2 ± 7.6%; APV = 2.8–6.6) were not significantly different from mild hyperphenylalaninemia, but there was a difference (p < .048) compared with classic PKU phenotypes.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Genetics, Biochemistry, Molecular Biology, Endocrinology, Diabetes and Metabolism, Endocrinology
Language:English
Date:1 September 2018
Deposited On:31 Jan 2019 13:42
Last Modified:31 Jan 2019 13:44
Publisher:Elsevier
ISSN:1096-7192
OA Status:Closed
Publisher DOI:https://doi.org/10.1016/j.ymgme.2018.06.011
PubMed ID:30037505
Project Information:
  • : FunderFP7
  • : Grant ID305444
  • : Project TitleRD-CONNECT - RD-CONNECT: An integrated platform connecting registries, biobanks and clinical bioinformatics for rare disease research

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