Structural and Functional Impact of Seven Missense Variants of Phenylalanine Hydroxylase

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F65269705%3A_____%2F19%3A00070998" target="_blank" >RIV/65269705:_____/19:00070998 - isvavai.cz</a>

Alternative codes found

RIV/00216224:14110/19:00109997

Result on the web

<a href="https://www.mdpi.com/2073-4425/10/6/459/htm" target="_blank" >https://www.mdpi.com/2073-4425/10/6/459/htm</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/genes10060459" target="_blank" >10.3390/genes10060459</a>

Result language

angličtina

Original language name

Structural and Functional Impact of Seven Missense Variants of Phenylalanine Hydroxylase

Original language description

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.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10603 - Genetics and heredity (medical genetics to be 3)

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2019

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Genes

ISSN

2073-4425

e-ISSN

—

Volume of the periodical

10

Issue of the periodical within the volume

6

Country of publishing house

CH - SWITZERLAND

Number of pages

13

Pages from-to

459

UT code for WoS article

000473797000054

EID of the result in the Scopus database

2-s2.0-85069430861