Informace o publikaci

Structural and Functional Impact of Seven Missense Variants of Phenylalanine Hydroxylase

Název česky Strukturální a funkční vliv sedmi missense patogennich sekvencnich variant na enzym fenylalanin hydroxylazu
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PECIMONOVA Martina KLUCKOVA Daniela CSICSAY František RÉBLOVÁ Kamila KRAHULEC Jan PROCHÁZKOVÁ Dagmar ŠKULTETY Ludovit KADASI Ludevít ŠOLTYSOVÁ Andrea

Rok publikování 2019
Druh Článek v odborném periodiku
Časopis / Zdroj Genes
Fakulta / Pracoviště MU

Lékařská fakulta

Citace
www https://www.mdpi.com/2073-4425/10/6/459
Doi http://dx.doi.org/10.3390/genes10060459
Klíčová slova Phenylalanine hydroxylase phenylketonuria BH4 functional studies missense variants
Popis 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.

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