Functional and structural characterisation of 5 missense mutations of the phenylalanine hydroxylase
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F17%3A00098089" target="_blank" >RIV/00216224:14740/17:00098089 - isvavai.cz</a>
Result on the web
<a href="http://www.elis.sk/index.php?page=shop.product_details&flypage=flypage.tpl&product_id=5357&category_id=132&option=com_virtuemart&vmcchk=1&Itemid=1" target="_blank" >http://www.elis.sk/index.php?page=shop.product_details&flypage=flypage.tpl&product_id=5357&category_id=132&option=com_virtuemart&vmcchk=1&Itemid=1</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.4149/gpb_2017003" target="_blank" >10.4149/gpb_2017003</a>
Alternative languages
Result language
angličtina
Original language name
Functional and structural characterisation of 5 missense mutations of the phenylalanine hydroxylase
Original language description
Phenylketonuria (PKU) and hyperphenylalaninemia (HPA) are a group of genetic disorders predominantly caused by mutations in the phenylalanine hydroxylase (PAH) gene. To date, more than 950 variants have been identified, however the pathogenic mechanism of many variants remains unknown. In this study, in silico prediction and in vitro prokaryotic and eukaryotic expression systems were used to functionally characterise five PAH missense variants (p.F233I, p.R270I, p.F331S, p.S350Y, and p.L358F) previously identified in Slovak and Czech patients. p.F233I, p.R270I, and p.S350Y were classified as deleterious mutations since they showed no specific activity in functional assay and no response to chaperone co-expression. Protein levels of these PAH variants were very low when expressed in HepG2 cells, and only p.S350Y responded to BH4 precursor overload by significant increase in PAH monomer, probably due to reduced rate of protein degradation as the result of proper protein folding. Variants p.F331S and p.L358F exerted residual enzymatic activity in vitro. While the first can be classified as probably pathogenic due to its very low protein levels in HepG2 cells, the latter is considered to be mild mutation with protein levels of approximately 17.85% compared to wt PAH. Our findings contribute to better understanding of structure and function of PAH mutated enzymes and optimal treatment of PKU patients carrying these mutations using BH4 supplementation.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10600 - Biological sciences
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2017
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
General physiology and biophysics
ISSN
0231-5882
e-ISSN
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Volume of the periodical
36
Issue of the periodical within the volume
4
Country of publishing house
SK - SLOVAKIA
Number of pages
11
Pages from-to
361-371
UT code for WoS article
000412155000001
EID of the result in the Scopus database
2-s2.0-85029895227