Structural and Functional Impact of Seven Missense Variants of
Phenylalanine Hydroxylase

J 2019

Structural and Functional Impact of Seven Missense Variants of Phenylalanine Hydroxylase

PECIMONOVA, Martina, Daniela KLUCKOVA, František CSICSAY, Kamila RÉBLOVÁ, Jan KRAHULEC et. al.

Základní údaje

Originální název

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

Autoři

PECIMONOVA, Martina (703 Slovensko), Daniela KLUCKOVA (703 Slovensko), František CSICSAY (703 Slovensko), Kamila RÉBLOVÁ (203 Česká republika, domácí), Jan KRAHULEC (703 Slovensko), Dagmar PROCHÁZKOVÁ (203 Česká republika, domácí), Ludovit ŠKULTETY (703 Slovensko), Ludevít KADASI (703 Slovensko) a Andrea ŠOLTYSOVÁ (703 Slovensko, garant)

Vydání

Genes, Basilej, MDPI, 2019, 2073-4425

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10603 Genetics and heredity

Stát vydavatele

Švýcarsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 3.759

Kód RIV

RIV/00216224:14110/19:00109997

Organizační jednotka

Lékařská fakulta

DOI

http://dx.doi.org/10.3390/genes10060459

UT WoS

000473797000054

Klíčová slova česky

fenylalnin hydroxylaza fenylketonurie BH4 funkční studie missense varianty

Klíčová slova anglicky

Phenylalanine hydroxylase phenylketonuria BH4 functional studies missense variants

Štítky

14110317, podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 11. 5. 2020 09:22, Mgr. Tereza Miškechová

Anotace

V originále

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.

Citovat

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. Genes. Basilej: MDPI, 2019, roč. 10, č. 6, s. 1-13. ISSN 2073-4425. Dostupné z: https://dx.doi.org/10.3390/genes10060459.

@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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