Molecular genetics and genotype-based estimation of BH4-responsiveness in serbian PKU patients: Spotlight on phenotypic implications of p.L48S
Само за регистроване кориснике
2012
Аутори
Đorđević, M.Klaassen, Kristel
Sarajlija, A.
Tošić, Nataša
Zukić, Branka
Kecman, B.
Ugrin, Milena
Spasovski, Vesna
Pavlović, Sonja
Stojiljković, Maja
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
Phenylketonuria (PKU) is caused by mutations in the gene encoding phenylalanine hydroxylase (PAH) enzyme. Here, we report the updated spectrum of PAH mutations in 61 Serbian PKU patients. By using both DGGE/DNA sequencing and PCR-RFLP, we identified 26 disease-causing mutations (detection rate 99%). The most frequent ones were p.L48S (31%), p.R408W (16.4%), p.P281L (6%), p.E390G (5.2%), and p.I306V (5.2%). Homozygosity value indicated high heterogeneity of Serbian population. To overcome possible pitfalls of patients’ phenotypic classification, we used two parameters: pretreatment/maximal phenylalanine blood concentration and Phe tolerance. The two phenotypes did not match only for patients with p.L48S. Therefore, we used Mann-Whitney statistical test to compare pretreatment/maximal blood Phe concentration and Phe tolerance detected in patients with p.[L48S];[null] and p.[missense];[null] genotypes. For patients with p.L48S, our results implied that Phe tolerance is a better parameter ...for phenotypic classification. Also, Fisher’s exact test was used to compare p.L48S effect on phenotype of homozygous and functionally hemizygous patients. Our findings showed that effect of p.L48S was altered in functional hemizygotes. Moreover, phenotypic inconsistency found in homozygotes suggested that interallelic complementation and/or additional factors play a role in genotype-phenotype correlation. Since BH4-supplementation therapy is not available in Serbia, we made the first estimation of its potential benefit based on patients’ genotypes. In the analyzed cohort, the total frequency of BH4-responsive mutations was 52.6%. Furthermore, we found a significant number of genotypes (26.2% BH4-responsive and 51% probably BH4-responsive) that may respond to BH4 therapy. This led us to a conclusion that BH4-supplementation therapy could bring benefit to Serbian PKU patients.
Извор:
JIMD Reports, 2012, 9, 49-58Издавач:
- Springer
Финансирање / пројекти:
- Acknowledgments This work has been funded by the Ministry of Education and Science, Republic of Serbia, grant No. III 41004.
DOI: 10.1007/8904_2012_178
ISSN: 2192-8304
PubMed: 23430547
Scopus: 2-s2.0-84882446283
Институција/група
Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Đorđević, M. AU - Klaassen, Kristel AU - Sarajlija, A. AU - Tošić, Nataša AU - Zukić, Branka AU - Kecman, B. AU - Ugrin, Milena AU - Spasovski, Vesna AU - Pavlović, Sonja AU - Stojiljković, Maja PY - 2012 UR - https://imagine.imgge.bg.ac.rs/handle/123456789/667 AB - Phenylketonuria (PKU) is caused by mutations in the gene encoding phenylalanine hydroxylase (PAH) enzyme. Here, we report the updated spectrum of PAH mutations in 61 Serbian PKU patients. By using both DGGE/DNA sequencing and PCR-RFLP, we identified 26 disease-causing mutations (detection rate 99%). The most frequent ones were p.L48S (31%), p.R408W (16.4%), p.P281L (6%), p.E390G (5.2%), and p.I306V (5.2%). Homozygosity value indicated high heterogeneity of Serbian population. To overcome possible pitfalls of patients’ phenotypic classification, we used two parameters: pretreatment/maximal phenylalanine blood concentration and Phe tolerance. The two phenotypes did not match only for patients with p.L48S. Therefore, we used Mann-Whitney statistical test to compare pretreatment/maximal blood Phe concentration and Phe tolerance detected in patients with p.[L48S];[null] and p.[missense];[null] genotypes. For patients with p.L48S, our results implied that Phe tolerance is a better parameter for phenotypic classification. Also, Fisher’s exact test was used to compare p.L48S effect on phenotype of homozygous and functionally hemizygous patients. Our findings showed that effect of p.L48S was altered in functional hemizygotes. Moreover, phenotypic inconsistency found in homozygotes suggested that interallelic complementation and/or additional factors play a role in genotype-phenotype correlation. Since BH4-supplementation therapy is not available in Serbia, we made the first estimation of its potential benefit based on patients’ genotypes. In the analyzed cohort, the total frequency of BH4-responsive mutations was 52.6%. Furthermore, we found a significant number of genotypes (26.2% BH4-responsive and 51% probably BH4-responsive) that may respond to BH4 therapy. This led us to a conclusion that BH4-supplementation therapy could bring benefit to Serbian PKU patients. PB - Springer T2 - JIMD Reports T1 - Molecular genetics and genotype-based estimation of BH4-responsiveness in serbian PKU patients: Spotlight on phenotypic implications of p.L48S EP - 58 SP - 49 VL - 9 DO - 10.1007/8904_2012_178 ER -
@article{ author = "Đorđević, M. and Klaassen, Kristel and Sarajlija, A. and Tošić, Nataša and Zukić, Branka and Kecman, B. and Ugrin, Milena and Spasovski, Vesna and Pavlović, Sonja and Stojiljković, Maja", year = "2012", abstract = "Phenylketonuria (PKU) is caused by mutations in the gene encoding phenylalanine hydroxylase (PAH) enzyme. Here, we report the updated spectrum of PAH mutations in 61 Serbian PKU patients. By using both DGGE/DNA sequencing and PCR-RFLP, we identified 26 disease-causing mutations (detection rate 99%). The most frequent ones were p.L48S (31%), p.R408W (16.4%), p.P281L (6%), p.E390G (5.2%), and p.I306V (5.2%). Homozygosity value indicated high heterogeneity of Serbian population. To overcome possible pitfalls of patients’ phenotypic classification, we used two parameters: pretreatment/maximal phenylalanine blood concentration and Phe tolerance. The two phenotypes did not match only for patients with p.L48S. Therefore, we used Mann-Whitney statistical test to compare pretreatment/maximal blood Phe concentration and Phe tolerance detected in patients with p.[L48S];[null] and p.[missense];[null] genotypes. For patients with p.L48S, our results implied that Phe tolerance is a better parameter for phenotypic classification. Also, Fisher’s exact test was used to compare p.L48S effect on phenotype of homozygous and functionally hemizygous patients. Our findings showed that effect of p.L48S was altered in functional hemizygotes. Moreover, phenotypic inconsistency found in homozygotes suggested that interallelic complementation and/or additional factors play a role in genotype-phenotype correlation. Since BH4-supplementation therapy is not available in Serbia, we made the first estimation of its potential benefit based on patients’ genotypes. In the analyzed cohort, the total frequency of BH4-responsive mutations was 52.6%. Furthermore, we found a significant number of genotypes (26.2% BH4-responsive and 51% probably BH4-responsive) that may respond to BH4 therapy. This led us to a conclusion that BH4-supplementation therapy could bring benefit to Serbian PKU patients.", publisher = "Springer", journal = "JIMD Reports", title = "Molecular genetics and genotype-based estimation of BH4-responsiveness in serbian PKU patients: Spotlight on phenotypic implications of p.L48S", pages = "58-49", volume = "9", doi = "10.1007/8904_2012_178" }
Đorđević, M., Klaassen, K., Sarajlija, A., Tošić, N., Zukić, B., Kecman, B., Ugrin, M., Spasovski, V., Pavlović, S.,& Stojiljković, M.. (2012). Molecular genetics and genotype-based estimation of BH4-responsiveness in serbian PKU patients: Spotlight on phenotypic implications of p.L48S. in JIMD Reports Springer., 9, 49-58. https://doi.org/10.1007/8904_2012_178
Đorđević M, Klaassen K, Sarajlija A, Tošić N, Zukić B, Kecman B, Ugrin M, Spasovski V, Pavlović S, Stojiljković M. Molecular genetics and genotype-based estimation of BH4-responsiveness in serbian PKU patients: Spotlight on phenotypic implications of p.L48S. in JIMD Reports. 2012;9:49-58. doi:10.1007/8904_2012_178 .
Đorđević, M., Klaassen, Kristel, Sarajlija, A., Tošić, Nataša, Zukić, Branka, Kecman, B., Ugrin, Milena, Spasovski, Vesna, Pavlović, Sonja, Stojiljković, Maja, "Molecular genetics and genotype-based estimation of BH4-responsiveness in serbian PKU patients: Spotlight on phenotypic implications of p.L48S" in JIMD Reports, 9 (2012):49-58, https://doi.org/10.1007/8904_2012_178 . .