TY  - JOUR
AU  - Karan-Đurašević, Teodora
AU  - Đorđević, Maja
AU  - Skakić, Anita
AU  - Desviat, Lourdes R.
AU  - Pavlović, Sonja
AU  - Perez, Belen
AU  - Stojiljković, Maja
PY  - 2018
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1140
AB  - Treatment with tetrahydrobiopterin (BH4) is the latest therapeutic option approved for patients with phenylketonuria (PKU)-one of the most frequent inborn metabolic diseases. PKU or phenylalanine hydroxylase (PAH) deficiency is caused by mutations in the PAH gene. Given that some PAH mutations are responsive to BH4 treatment while others are non-responsive, for every novel mutation that is discovered it is essential to confirm its pathogenic effect and to assess its responsiveness to a BH4 treatment in vitro, before the drug is administered to patients. We found a c.676C gt A (p.Gln226Lys) mutation in the PAH gene in two unrelated patients with PKU. The corresponding aberrant protein has never been functionally characterized in vitro and its response to BH4 treatment is unknown. Computational analyses proposed that glutamine at position 226 is an important, evolutionary conserved amino acid while the substitution with lysine probably disturbs tertiary protein structure and impacts posttranslational PAH modifications. Using hepatoma cellular model, we demonstrated that the amount of mutant p.Gln226Lys PAH detected by Western blot was only 1.2% in comparison to wild-type PAH. The addition of sepiapterin, intracellular precursor of BH4, did not increase PAH protein yield thus marking p.Gln226Lys as BH4-non-responsive mutation. Therefore, computational, experimental, and clinical data were all in accordance showing that p.Gln226Lys is a severe pathogenic PAH mutation. Its non-responsiveness to BH4 treatment in hepatoma cellular model should be considered when deciding treatment options for PKU patients carrying this mutation. Consequently, our study will facilitate clinical genetic practice, particularly genotype-based stratification of PKU treatment.
PB  - Springer/Plenum Publishers, New York
T2  - Biochemical Genetics
T1  - Functional Characterization of Novel Phenylalanine Hydroxylase p.Gln226Lys Mutation Revealed Its Non-responsiveness to Tetrahydrobiopterin Treatment in Hepatoma Cellular Model
EP  - 541
IS  - 5
SP  - 533
VL  - 56
DO  - 10.1007/s10528-018-9858-5
ER  - 

@article{
author = "Karan-Đurašević, Teodora and Đorđević, Maja and Skakić, Anita and Desviat, Lourdes R. and Pavlović, Sonja and Perez, Belen and Stojiljković, Maja",
year = "2018",
abstract = "Treatment with tetrahydrobiopterin (BH4) is the latest therapeutic option approved for patients with phenylketonuria (PKU)-one of the most frequent inborn metabolic diseases. PKU or phenylalanine hydroxylase (PAH) deficiency is caused by mutations in the PAH gene. Given that some PAH mutations are responsive to BH4 treatment while others are non-responsive, for every novel mutation that is discovered it is essential to confirm its pathogenic effect and to assess its responsiveness to a BH4 treatment in vitro, before the drug is administered to patients. We found a c.676C gt A (p.Gln226Lys) mutation in the PAH gene in two unrelated patients with PKU. The corresponding aberrant protein has never been functionally characterized in vitro and its response to BH4 treatment is unknown. Computational analyses proposed that glutamine at position 226 is an important, evolutionary conserved amino acid while the substitution with lysine probably disturbs tertiary protein structure and impacts posttranslational PAH modifications. Using hepatoma cellular model, we demonstrated that the amount of mutant p.Gln226Lys PAH detected by Western blot was only 1.2% in comparison to wild-type PAH. The addition of sepiapterin, intracellular precursor of BH4, did not increase PAH protein yield thus marking p.Gln226Lys as BH4-non-responsive mutation. Therefore, computational, experimental, and clinical data were all in accordance showing that p.Gln226Lys is a severe pathogenic PAH mutation. Its non-responsiveness to BH4 treatment in hepatoma cellular model should be considered when deciding treatment options for PKU patients carrying this mutation. Consequently, our study will facilitate clinical genetic practice, particularly genotype-based stratification of PKU treatment.",
publisher = "Springer/Plenum Publishers, New York",
journal = "Biochemical Genetics",
title = "Functional Characterization of Novel Phenylalanine Hydroxylase p.Gln226Lys Mutation Revealed Its Non-responsiveness to Tetrahydrobiopterin Treatment in Hepatoma Cellular Model",
pages = "541-533",
number = "5",
volume = "56",
doi = "10.1007/s10528-018-9858-5"
}

Karan-Đurašević, T., Đorđević, M., Skakić, A., Desviat, L. R., Pavlović, S., Perez, B.,& Stojiljković, M.. (2018). Functional Characterization of Novel Phenylalanine Hydroxylase p.Gln226Lys Mutation Revealed Its Non-responsiveness to Tetrahydrobiopterin Treatment in Hepatoma Cellular Model. in Biochemical Genetics
Springer/Plenum Publishers, New York., 56(5), 533-541.
https://doi.org/10.1007/s10528-018-9858-5

Karan-Đurašević T, Đorđević M, Skakić A, Desviat LR, Pavlović S, Perez B, Stojiljković M. Functional Characterization of Novel Phenylalanine Hydroxylase p.Gln226Lys Mutation Revealed Its Non-responsiveness to Tetrahydrobiopterin Treatment in Hepatoma Cellular Model. in Biochemical Genetics. 2018;56(5):533-541.
doi:10.1007/s10528-018-9858-5 .

Karan-Đurašević, Teodora, Đorđević, Maja, Skakić, Anita, Desviat, Lourdes R., Pavlović, Sonja, Perez, Belen, Stojiljković, Maja, "Functional Characterization of Novel Phenylalanine Hydroxylase p.Gln226Lys Mutation Revealed Its Non-responsiveness to Tetrahydrobiopterin Treatment in Hepatoma Cellular Model" in Biochemical Genetics, 56, no. 5 (2018):533-541,
https://doi.org/10.1007/s10528-018-9858-5 . .

TY  - JOUR
AU  - Stojiljković, Maja
AU  - Klaassen, Kristel
AU  - Đorđević, Maja
AU  - Sarajlija, Adrijan
AU  - Kecman, Bozica
AU  - Ugrin, Milena
AU  - Zukić, Branka
AU  - Desviat, Lourdes R.
AU  - Pavlović, Sonja
AU  - Perez, Belen
PY  - 2015
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/882
AB  - Hyperphenylalaninemia (HPA) [phenylketonuria (PKU) and tetrahydrobiopterin (BH4) deficiencies] is rare inborn metabolic disease characterized by elevated phenylalanine level in body fluids. In Serbia, 62 HPA patients have been identified through newborn screening since 1983. However, pterin pattern analysis is not performed. We present a patient initially diagnosed and treated as classical PKU. At 3 years of age, during infection with H1N1 influenza A virus, the patient first developed a neurologic crisis with encephalopathy and dystonic movements. We suspected that the patient is the first case of BH4 deficiency identified in Serbia. Genetic analyses showed that the patient does not have disease- causing variants of the PAH gene and carries a p. Asp136Val mutation in homozygous state in the PTS gene. For patients with treatable rare diseases, like PKU and BH4 deficiencies, correct diagnosis is crucial for the implementation of optimal treatment. If biochemical tests needed for differential diagnosis are not available, our experience emphasizes the necessity of immediate genetic testing after newborn screening.
PB  - Walter De Gruyter Gmbh, Berlin
T2  - Journal of Pediatric Endocrinology & Metabolism
T1  - Tetrahydrobiopterin deficiency among Serbian patients presenting with hyperphenylalaninemia
EP  - 480
IS  - 3-4
SP  - 477
VL  - 28
DO  - 10.1515/jpem-2014-0297
ER  - 

@article{
author = "Stojiljković, Maja and Klaassen, Kristel and Đorđević, Maja and Sarajlija, Adrijan and Kecman, Bozica and Ugrin, Milena and Zukić, Branka and Desviat, Lourdes R. and Pavlović, Sonja and Perez, Belen",
year = "2015",
abstract = "Hyperphenylalaninemia (HPA) [phenylketonuria (PKU) and tetrahydrobiopterin (BH4) deficiencies] is rare inborn metabolic disease characterized by elevated phenylalanine level in body fluids. In Serbia, 62 HPA patients have been identified through newborn screening since 1983. However, pterin pattern analysis is not performed. We present a patient initially diagnosed and treated as classical PKU. At 3 years of age, during infection with H1N1 influenza A virus, the patient first developed a neurologic crisis with encephalopathy and dystonic movements. We suspected that the patient is the first case of BH4 deficiency identified in Serbia. Genetic analyses showed that the patient does not have disease- causing variants of the PAH gene and carries a p. Asp136Val mutation in homozygous state in the PTS gene. For patients with treatable rare diseases, like PKU and BH4 deficiencies, correct diagnosis is crucial for the implementation of optimal treatment. If biochemical tests needed for differential diagnosis are not available, our experience emphasizes the necessity of immediate genetic testing after newborn screening.",
publisher = "Walter De Gruyter Gmbh, Berlin",
journal = "Journal of Pediatric Endocrinology & Metabolism",
title = "Tetrahydrobiopterin deficiency among Serbian patients presenting with hyperphenylalaninemia",
pages = "480-477",
number = "3-4",
volume = "28",
doi = "10.1515/jpem-2014-0297"
}

Stojiljković, M., Klaassen, K., Đorđević, M., Sarajlija, A., Kecman, B., Ugrin, M., Zukić, B., Desviat, L. R., Pavlović, S.,& Perez, B.. (2015). Tetrahydrobiopterin deficiency among Serbian patients presenting with hyperphenylalaninemia. in Journal of Pediatric Endocrinology & Metabolism
Walter De Gruyter Gmbh, Berlin., 28(3-4), 477-480.
https://doi.org/10.1515/jpem-2014-0297

Stojiljković M, Klaassen K, Đorđević M, Sarajlija A, Kecman B, Ugrin M, Zukić B, Desviat LR, Pavlović S, Perez B. Tetrahydrobiopterin deficiency among Serbian patients presenting with hyperphenylalaninemia. in Journal of Pediatric Endocrinology & Metabolism. 2015;28(3-4):477-480.
doi:10.1515/jpem-2014-0297 .

Stojiljković, Maja, Klaassen, Kristel, Đorđević, Maja, Sarajlija, Adrijan, Kecman, Bozica, Ugrin, Milena, Zukić, Branka, Desviat, Lourdes R., Pavlović, Sonja, Perez, Belen, "Tetrahydrobiopterin deficiency among Serbian patients presenting with hyperphenylalaninemia" in Journal of Pediatric Endocrinology & Metabolism, 28, no. 3-4 (2015):477-480,
https://doi.org/10.1515/jpem-2014-0297 . .