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@article{1542176, author = {Pecimonova, Martina and Kluckova, Daniela and Csicsay, František and Réblová, Kamila and Krahulec, Jan and Procházková, Dagmar and Škultety, Ludovit and Kadasi, Ludevít and Šoltysová, Andrea}, article_location = {Basilej}, article_number = {6}, doi = {http://dx.doi.org/10.3390/genes10060459}, keywords = {Phenylalanine hydroxylase phenylketonuria BH4 functional studies missense variants}, language = {eng}, issn = {2073-4425}, journal = {Genes}, title = {Structural and Functional Impact of Seven Missense Variants of Phenylalanine Hydroxylase}, url = {https://www.mdpi.com/2073-4425/10/6/459}, volume = {10}, year = {2019} }
TY - JOUR ID - 1542176 AU - Pecimonova, Martina - Kluckova, Daniela - Csicsay, František - Réblová, Kamila - Krahulec, Jan - Procházková, Dagmar - Škultety, Ludovit - Kadasi, Ludevít - Šoltysová, Andrea PY - 2019 TI - Structural and Functional Impact of Seven Missense Variants of Phenylalanine Hydroxylase JF - Genes VL - 10 IS - 6 SP - 1-13 EP - 1-13 PB - MDPI SN - 20734425 KW - Phenylalanine hydroxylase phenylketonuria BH4 functional studies missense variants UR - https://www.mdpi.com/2073-4425/10/6/459 L2 - https://www.mdpi.com/2073-4425/10/6/459 N2 - The molecular genetics of well-characterized inherited diseases, such as phenylketonuria (PKU) and hyperphenylalaninemia (HPA) predominantly caused by mutations in the phenylalanine hydroxylase (PAH) gene, is often complicated by the identification of many novel variants, often with no obvious impact on the associated disorder. To date, more than 1100 PAH variants have been identified of which a substantial portion have unknown clinical significance. In this work, we study the functionality of seven yet uncharacterized PAH missense variants p.Asn167Tyr, p.Thr200Asn, p.Asp229Gly, p.Gly239Ala, p.Phe263Ser, p.Ala342Pro, and p.Ile406Met first identified in the Czech PKU/HPA patients. From all tested variants, three of them, namely p.Asn167Tyr, p.Thr200Asn, and p.Ile406Met, exerted residual enzymatic activity in vitro similar to wild type (WT) PAH, however, when expressed in HepG2 cells, their protein level reached a maximum of 72.1% ± 4.9%, 11.2% ± 4.2%, and 36.6% ± 7.3% compared to WT PAH, respectively. Remaining variants were null with no enzyme activity and decreased protein levels in HepG2 cells. The chaperone-like effect of applied BH4 precursor increased protein level significantly for p.Asn167Tyr, p.Asp229Gly, p.Ala342Pro, and p.Ile406Met. Taken together, our results of functional characterization in combination with in silico prediction suggest that while p.Asn167Tyr, p.Thr200Asn, and p.Ile406Met PAH variants have a mild impact on the protein, p.Asp229Gly, p.Gly239Ala, p.Phe263Ser, and p.Ala342Pro severely affect protein structure and function. ER -
PECIMONOVA, Martina, Daniela KLUCKOVA, František CSICSAY, Kamila RÉBLOVÁ, Jan KRAHULEC, Dagmar PROCHÁZKOVÁ, Ludovit ŠKULTETY, Ludevít KADASI a Andrea ŠOLTYSOVÁ. Structural and Functional Impact of Seven Missense Variants of Phenylalanine Hydroxylase. \textit{Genes}. Basilej: MDPI, 2019, roč.~10, č.~6, s.~1-13. ISSN~2073-4425. Dostupné z: https://dx.doi.org/10.3390/genes10060459.
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