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@article{1394040,
author = {Pecimonova, Martina and Polak, Emil and Csicsay, Frantisek and Réblová, Kamila and Stojiljkovic, Maja and Levarski, Zdenko and Skultety, Ludovit and Kadasi, Ludevit and Soltysova, Andrea},
article_location = {BRATISLAVA},
article_number = {4},
doi = {http://dx.doi.org/10.4149/gpb_2017003},
keywords = {PAH mutations; Phenylketonuria; Specific activity; Chaperons; Functional study},
language = {eng},
issn = {0231-5882},
journal = {General physiology and biophysics},
title = {Functional and structural characterisation of 5 missense mutations of the phenylalanine hydroxylase},
url = {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},
volume = {36},
year = {2017}
}
TY - JOUR
ID - 1394040
AU - Pecimonova, Martina - Polak, Emil - Csicsay, Frantisek - Réblová, Kamila - Stojiljkovic, Maja - Levarski, Zdenko - Skultety, Ludovit - Kadasi, Ludevit - Soltysova, Andrea
PY - 2017
TI - Functional and structural characterisation of 5 missense mutations of the phenylalanine hydroxylase
JF - General physiology and biophysics
VL - 36
IS - 4
SP - 361-371
EP - 361-371
PB - General Physiol and Biophysic
SN - 02315882
KW - PAH mutations
KW - Phenylketonuria
KW - Specific activity
KW - Chaperons
KW - Functional study
UR - 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
L2 - 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
N2 - 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.
ER -
PECIMONOVA, Martina, Emil POLAK, Frantisek CSICSAY, Kamila RÉBLOVÁ, Maja STOJILJKOVIC, Zdenko LEVARSKI, Ludovit SKULTETY, Ludevit KADASI and Andrea SOLTYSOVA. Functional and structural characterisation of 5 missense mutations of the phenylalanine hydroxylase. \textit{General physiology and biophysics}. BRATISLAVA: General Physiol and Biophysic, 2017, vol.~36, No~4, p.~361-371. ISSN~0231-5882. Available from: https://dx.doi.org/10.4149/gpb\_{}2017003.
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