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Journal of Medical Biochemistry

The Journal of Society of Medical Biochemists of Serbia


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1452-8266
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Molecular Diagnosis of Phenylketonuria: From Defective Protein to Disease-Causing Gene Mutation

Sonja Pavlović1 / Maja Stojiljković1

Institute of Molecular Genetics and Genetic Engineering, Belgrade, Serbia1

This content is open access.

Citation Information: Journal of Medical Biochemistry. Volume 28, Issue 4, Pages 262–267, ISSN (Online) 1452-8266, ISSN (Print) 1452-8258, DOI: 10.2478/v10011-009-0021-z, November 2009

Publication History

Published Online:
2009-11-05

Molecular Diagnosis of Phenylketonuria: From Defective Protein to Disease-Causing Gene Mutation

Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism, with an average incidence of 1/10000 in Caucasians. PKU is caused by more than 500 mutations in the phenylalanine hydroxylase gene (PAH) which result in phenylalanine hydroxylase (PAH) enzyme deficiency. Two approaches, in vitro expression analysis of mutant PAH and genotype-phenotype correlation study, are used for the assessment of severity of PAH mutations. It has been shown that there is a significant correlation between mutant PAH genotypes and PKU phenotypes. As a result, the molecular diagnosis is completely shifted toward the detection of mutations in the phenylalanine hydroxylase gene. The study of the molecular basis of PKU in Serbia included identification of the spectrum and frequency of PAH mutations in Serbian PKU patients and genotype-phenotype correlation analysis. By using both PCR-RFLP and »broad range« DGGE/DNA sequencing analysis, the mutation detection rate reached 97%. Thus, the base for molecular diagnosis, genetic counseling and selection of BH4-responsive PKU patients in Serbia was created.

Molekularna Dijagnoza Fenilketonurije: Od Promena U Proteinu Do Mutacija U Genu

Fenilketonurija (PKU) najčešći je urođeni metabolički poremećaj u populaciji belaca (1/10000). Fenilketonurija nastaje kao posledica više od 500 mutacija u genu za fenilalanin hidroksilazu (PAH) koje dovode do deficijencije u aktivnosti enzima fenilalanin hidroksilaze (PAH). Pomoću in vitro ekspresione analize mutiranog enzima PAH i genotip-fenotip korelacije procenjuje se težina mutacija. Pokazano je da postoji značajna korelacija između genotipova u kojima su prisutni mutirani aleli gena PAH i fenotipa PKU. Zbog toga je detekcija mutacija u genu za fenilalanin hidroksilazu sastavni deo moderne dijagnostike PKU. Studija molekularne osnove fenilketonurije u Srbiji obuhvatila je identifikaciju spektra i frekvencije mutacija PAH i analizu korelacije genotipa i fenotipa pacijenata. Kombinovanjem metoda, PCR-RFLP, DGGE širokog spektra i DNK sekvenciranja, postignut je nivo detekcije mutacija od 97%. Na taj način je u Srbiji postavljena osnova za molekularnu dijagnostiku, genetsko savetovanje i odabir pacijenata sa fenilketonurijom kojima bi BH4 terapija bila od koristi.

Keywords: phenylalanine hydroxylase; phenylalanine hydroxylase gene mutations; phenotype-genotype correlation; phenylketonuria; tetrahydrobiopterin

Keywords: fenilalanin hidroksilaza; korelacija fenotipgenotip; mutacije u genu za fenilalanin hidroksilazu; fenilketonurija; tetrahidrobiopterin

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