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Verfasst von:Trunzo, Roberta [VerfasserIn]   i
 Shen, Nan [VerfasserIn]   i
 Jung-Klawitter, Sabine [VerfasserIn]   i
 Blau, Nenad [VerfasserIn]   i
Titel:In vitro residual activity of phenylalanine hydroxylase variants and correlation with metabolic phenotypes in PKU
Verf.angabe:Roberta Trunzo, Rosa Santacroce, Nan Shen, Sabine Jung-Klawitter, Angelica Leccese, Giuseppe De Girolamo, Maurizio Margaglione, Nenad Blau
E-Jahr:2016
Jahr:13 September 2016
Umfang:6 S.
Fussnoten:Gesehen am 07.09.2017
Titel Quelle:Enthalten in: Gene
Ort Quelle:Amsterdam : Elsevier, 1976
Jahr Quelle:2016
Band/Heft Quelle:594(2016), 1, Seite 138-143
ISSN Quelle:1879-0038
Abstract:Hyperphenylalaninemias (HPAs) are genetic diseases predominantly caused by a wide range of variants in the phenylalanine hydroxylase (PAH) gene. In vitro expression analysis of PAH variants offers the opportunity to elucidate the molecular mechanisms involved in HPAs and to clarify whether a disease-associated variant is genuinely pathogenic, while investigating the severity of a metabolic phenotype, and determining how a variant exerts its deleterious effects on the PAH enzyme. To study the effects of gene variants on PAH activity, we investigated eight variants: c.611A > G (p.Y204C), c.635T > C (p.L212P), c.746T > C (p.L249P), c.745C > T (p.L249F), c.809G > A (p.R270K), c.782G > C (p.R261P), c.587C > A (p.S196Y) and c.1139C > T (p.T380M), associated with different phenotypic groups. Transient expression of mutant full-length cDNAs in COS-7 cells yielded PAH proteins with PAH activity levels between 7% and 51% compared to the wild-type enzyme. With one exception (p.Y204C, which had no significant impact on PAH function), lower PAH activity was associated with a more severe phenotype (e.g. p.L249P with 7% PAH activity, 100% of classic PKU and no BH4 responsiveness), while higher activity correlated with milder phenotypes (e.g. p.T380M with 28% PAH activity, 97% of mild HPA and 83% of BH4 responsiveness). The results of the in vitro residual PAH activity have major implications, both for our understanding of genotype-phenotype correlations, and thereby existing inconsistencies, but also for the elucidation of the molecular basis of tetrahydrobiopterin (BH4) responsiveness.
DOI:doi:10.1016/j.gene.2016.09.015
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

Volltext ; Verlag: http://dx.doi.org/10.1016/j.gene.2016.09.015
 Volltext: http://www.sciencedirect.com/science/article/pii/S0378111916307314
 DOI: https://doi.org/10.1016/j.gene.2016.09.015
Datenträger:Online-Ressource
Sprache:eng
Sach-SW:In vitro expression
 Phenylalanine hydroxylase
 Phenylketonuria
 Tetrahydrobiopterin
K10plus-PPN:1563305550
Verknüpfungen:→ Zeitschrift

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