Abstract |
Specific mutations in the gene encoding phenylalanine hydroxylase (PAH), located on chromosome 12q22-24.1, are linked to tetrahydrobiopterin (BH4; sapropterin)-responsive phenylketonuria (PKU). Diagnosis is usually done through the newborn screening for PKU, followed by a BH4 loading test. So far, more than 60 mutant alleles, presenting with a substantial residual PAH activity (average approximately 47%), were identified in more than 500 patients worldwide. We investigated the predictive value of BH4-responsive PAH mutations in Croatian population. From a group of 127 PKU patients, 62 were selected (based on the genotype) as potentially BH4-responsive and 39 loaded with BH4 (20 mg/kg). The overall frequency of BH4-responsiveness (>30% blood phenylalanine reduction within 24 h) was 36% (14 out of 39 patients with 23 different genotypes), significantly less than expected. The best responders were patients with mild hyperphenylalaninemia (4/4; 100%), followed by mild PKU (8/9; 89%), and classical PKU (2/26; 8%). The most common BH(4)-responsive genotypes were p.E390G/p.R408W and p.P281L/p.E390G. These genotypes correspond for approximately >30% residual PAH activity. The p.E390G mutation was 100% associated with BH4-responsiveness, regardless of the second allele (p.R408W, p.P281L, p.F55Lfs, p.L249P). With regard to the predicted relative PAH activity of recombinantly expressed mutant alleles, there was a significant (p<0.002) difference between BH4-responders and non-responders. In a general Croatian PKU population, disease-causing mutations were identified on 226 alleles (99%). There were 35 different mutations: 21 missense, 8 splice site, 3 nonsense, 2 single nucleotide deletions, and 1 in-frame deletion. Four mutations are reported for the first time: p.E76D, p.L333P, p.G346E, and IVS8-2A>G. Five mutations accounted for over two-thirds of investigated alleles: p.L48S, p.R261Q, p.P281L, p.E390G, and p.R408W. Thus, the Croatian PKU population seems to be more homogenous than some other Mediterranean or Central European populations. This study reveals the importance of a full genotype for the prediction of BH4-responsiveness. In contrast to previous assumption and with exception of the p.E390G mutation, single allele mutations are not reliable for the selection of potential PKU candidates for pharmacological therapy with BH4.
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Authors | Iva Karacić, David Meili, Vladimir Sarnavka, Caroline Heintz, Beat Thöny, Danijela Petković Ramadza, Ksenija Fumić, Dusko Mardesić, Ivo Barić, Nenad Blau |
Journal | Molecular genetics and metabolism
(Mol Genet Metab)
Vol. 97
Issue 3
Pg. 165-71
(Jul 2009)
ISSN: 1096-7206 [Electronic] United States |
PMID | 19394257
(Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Biopterin
- Phenylalanine Hydroxylase
- sapropterin
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Topics |
- Adolescent
- Adult
- Alleles
- Biopterin
(administration & dosage, analogs & derivatives, pharmacology)
- Child
- Child, Preschool
- Croatia
- Female
- Genotype
- Humans
- Infant
- Male
- Mutation
(genetics)
- Phenylalanine Hydroxylase
(deficiency, genetics)
- White People
(genetics)
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