Genetic variants of the phenylalanine hydroxylase gene in patients with phenylketonuria in the northeast of Iran
-
Reza Jafarzadeh-Esfehani
,
Samaneh Vojdani
Abstract
Background
Phenylketonuria (PKU) is a common metabolic disorder with great burden if left untreated or undiagnosed. Genetic variations in the phenylalanine hydroxylase (PAH) gene may be widely varied across different regions of a country. By knowing the most common mutations, diagnostic work-ups will be offered sooner and with lower costs for patients. The present study defines the most common genetic variations in the PAH gene in Khorasan province of Iran.
Methods
The present cross-sectional study took place in Khorasan province of Iran within a 6-year period starting from 2012 to 2018. Every patient who had been referred as suspicious PKU cases or referred for prenatal diagnosis was included in the present study.
Results
A total number of 122 individuals with a mean age of 26.22 years were enrolled in the present study. The most frequent genetic variations in the PAH gene were c.1066-11G > A and c.143 T > C. Exon 7 carried the most genetic variations compared to any single exon. Also, three patients had compound heterozygous status for c.727 C > T/c.1066-11 G > A in exon 7 and 11 of the PAH gene.
Conclusions
Mutations in the PAH gene are widely varied among different populations, and our results confirmed this fact. Determination of the most prevalent mutations and polymorphisms in each region will reduce the time and cost of diagnosing such preventable diseases and will therefore reduce the disease burden.
Acknowledgments
None declared.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. El-Metwally A, Yousef Al-Ahaidib L, Ayman Sunqurah A, Al-Surimi K, Househ M, et al. The prevalence of phenylketonuria in Arab countries, Turkey, and Iran: a systematic review. J BioMed Res Int 2018;2018:12.10.1155/2018/7697210Suche in Google Scholar PubMed PubMed Central
2. Hanley WB. Adult phenylketonuria. Am J Med 2004;117:590–5.10.1016/j.amjmed.2004.03.042Suche in Google Scholar PubMed
3. Ghiasvand N, Aledavood A, Ghiasvand R, Borojeny FS,Aledavood A, et al. Prevalence of classical phenylketonuria in mentally retarded individuals in Iran. J Inherit Metab Dis 2009;32:283–7.10.1007/s10545-009-1222-9Suche in Google Scholar PubMed
4. Ganji F, Naseri H, Rostampour N, Sedighi M, Lotfizadeh M. Assessing the phenylketonuria screening program in newborns, Iran 2015–2016. Acta Med Iran 2018;56:49–55.Suche in Google Scholar
5. Pourfarzam M, Zadhoush FJ. Newborn screening for inherited metabolic disorders; news and views. J Res Med Sci 2013;18:801–8.Suche in Google Scholar
6. Eijgelshoven I, Demirdas S, Smith TA, van Loon JM, Latour S, et al. The time consuming nature of phenylketonuria: a cross-sectional study investigating time burden and costs of phenylketonuria in the Netherlands. Mol Genet Metab 2013;109:237–42.10.1016/j.ymgme.2013.05.003Suche in Google Scholar PubMed
7. Shirzadeh T, Saeidian AH, Bagherian H, Salehpour S, Setoodeh A, et al. Molecular genetics of a cohort of 635 cases of phenylketonuria in a consanguineous population. J Inherit Metab Dis 2018;41:1159–67.10.1007/s10545-018-0228-6Suche in Google Scholar PubMed
8. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16:1215.10.1093/nar/16.3.1215Suche in Google Scholar PubMed PubMed Central
9. Haeussler M, Zweig AS, Tyner C, Speir ML, Rosenbloom KR, et al. The UCSC Genome Browser database: 2019 update. Nucleic Acids Res 2019;47:D853–8.10.1093/nar/gky1095Suche in Google Scholar PubMed PubMed Central
10. Kopanos C, Tsiolkas V, Kouris A, Chapple CE, Albarca Aguilera M, et al. VarSome: the human genomic variant search engine. Bioinformatics 2018;35:1978–80.10.1093/bioinformatics/bty897Suche in Google Scholar PubMed PubMed Central
11. Alibakhshi RP, Moradi KM, Biglari MM, Shafieenia SM. Spectrum of phenylalanine hydroxylase gene mutations in Hamadan and Lorestan provinces of Iran and their associations with variable number of tandem repeat alleles. Iran J Med Sci 2018;43:318–23.10.1080/03630269.2019.1584114Suche in Google Scholar
12. Pey AL, Desviat LR, Gámez A, Ugarte M, Pérez B. Phenylketonuria: genotype–phenotype correlations based on expression analysis of structural and functional mutations in PAH. Hum Mutat 2003;21:370–8.10.1002/humu.10198Suche in Google Scholar PubMed
13. Wang T, Okano Y, Eisensmith RC, Fekete G, Schuler D, et al. Molecular genetics of PKU in eastern Europe: a nonsense mutation associated with haplotype 4 of the phenylalanine hydroxylase gene. Somat Cell Mol Genet 1990;16:85–90.10.1007/BF01650483Suche in Google Scholar PubMed
14. Rastegar Moghadam M, Shojaei A, Babaei V, Rohani F, Ghazi F. Mutation analysis of phenylalanine hydroxylase gene in Iranian patients with phenylketonuria. Med J Islam Repub Iran 2018;32:21.10.14196/mjiri.32.21Suche in Google Scholar
15. Chao HK, Hsiao KJ, Su TS. A silent mutation induces exon skipping in the phenylalanine hydroxylase gene in phenylketonuria. Hum Genet 2001;108:14–9.10.1007/s004390000435Suche in Google Scholar
16. Hamzehloei T, Hosseini SA, Vakili R, Mojarad M. Mutation spectrum of the PAH gene in the PKU patients from Khorasan Razavi province of Iran. Gene 2012;506:230–2.10.1016/j.gene.2012.06.043Suche in Google Scholar
17. Biglari A, Saffari F, Rashvand Z, Alizadeh S, Najafipour R, et al. Mutations of the phenylalanine hydroxylase gene in Iranian patients with phenylketonuria. Springerplus 2015;4:542.10.1186/s40064-015-1309-8Suche in Google Scholar
18. Jeannesson-Thivisol E, Feillet F, Chéry C, Perrin P, Battaglia-Hsu SF, et al. Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness. Orphanet J Rare Dis 2015;10:158.10.1186/s13023-015-0375-xSuche in Google Scholar
19. Hennermann JB, Vetter B, Wolf C, Windt E, Buhrdel P, et al. Phenylketonuria and hyperphenylalaninemia in eastern Germany: a characteristic molecular profile and 15 novel mutations. Hum Mutat 2000;15:254–60.10.1002/(SICI)1098-1004(200003)15:3<254::AID-HUMU6>3.0.CO;2-WSuche in Google Scholar
20. Carter KC, Byck S, Waters PJ, Richards B, Nowacki PM, et al. Mutation at the phenylalanine hydroxylase gene (PAH) and its use to document population genetic variation: the Quebec experience. Eur J Hum Genet 1998;6:61–70.10.1038/sj.ejhg.5200153Suche in Google Scholar
21. Esfahani MS, Vallian S. A comprehensive study of phenylalanine hydroxylase gene mutations in the Iranian phenylketonuria patients. Eur J Med Genet 2019;62:103559.10.1016/j.ejmg.2018.10.011Suche in Google Scholar
22. Ajami N, Kazeminezhad SR, Foroughmand AM, Hasanpour M, Aminzadeh M. A preliminary mutation analysis of phenylketonuria in southwest Iran. Genet Mol Res 2013;12:4958–66.10.4238/2013.October.24.7Suche in Google Scholar
23. Guldberg P, Romano V, Ceratto N, Bosco P, Ciuna M, et al. Mutational spectrum of phenylalanine hydroxylase deficiency in Sicily: implications for diagnosis of hyperphenylalaninemia in southern Europe. Hum Mol Genet 1993;2:1703–7.10.1093/hmg/2.10.1703Suche in Google Scholar
24. Guldberg P, Levy HL, Hanley WB, Koch R, Matalon R, et al. Phenylalanine hydroxylase gene mutations in the United States: report from the Maternal PKU Collaborative Study. Am J Hum Genet 1996;59:84–94.Suche in Google Scholar
25. Lyonnet S, Caillaud C, Rey F, Berthelon M, Frezal J, et al. Molecular genetics of phenylketonuria in Mediterranean countries: a mutation associated with partial phenylalanine hydroxylase deficiency. Am J Hum Genet 1989;44:511–7.Suche in Google Scholar
26. Dobrowolski SF, Heintz C, Miller T, Ellingson C, Ellingson C, et al. Molecular genetics and impact of residual in vitro phenylalanine hydroxylase activity on tetrahydrobiopterin responsiveness in Turkish PKU population. Mol Genet Metab 2011;102:116–21.10.1016/j.ymgme.2010.11.158Suche in Google Scholar PubMed
27. Zare-Karizi S, Hosseini-Mazinani SM, Khazaei-Koohpar Z, Seifati SM, Shahsavan-Behboodi B, et al. Mutation spectrum of phenylketonuria in Iranian population. Mol Genet Metab 2011;102:29–32.10.1016/j.ymgme.2010.09.001Suche in Google Scholar PubMed
©2020 Walter de Gruyter GmbH, Berlin/Boston
Artikel in diesem Heft
- Frontmatter
- Original Articles
- Vitamin D status in Israeli pediatric type 1 diabetes patients: the AWeSoMe Study Group experience and literature review
- Metabolic features and changes in glucose-induced serum glucagon-like peptide-1 levels in children with hypothalamic obesity
- Assessment of intima-media thickness of the carotid artery and intraluminal diameter of the brachial artery as cardiovascular risk markers in Brazilian adolescents with overweight or obesity
- The role of LCPUFA-ω3 on the obesity-associated hyperandrogenemia of pubertal girls: secondary analysis of a randomized clinical trial
- Genetic variants of the phenylalanine hydroxylase gene in patients with phenylketonuria in the northeast of Iran
- Oral health status of children with phenylketonuria
- Birth weight related blood concentrations of the neurotransmission amino acids glutamine plus glutamate, phenylalanine and tyrosine in full-term breastfed infants perinatally
- Hyperthyrotropinemia is common in preterm infants who are born small for gestational age
- Radioactive iodine therapy for pediatric Graves’ disease: a single-center experience over a 10-year period
- The decision-making levels of urine tetrasaccharide for the diagnosis of Pompe disease in the Turkish population
- A questionnaire study on sleep disturbances associated with Prader-Willi syndrome
- Body size measurements, digit ratio (2D:4D) and oestrogen and progesterone receptors’ expressions in juvenile gigantomastia
- The effect of celiac disease and gluten-free diet on pubertal development: a two-center study
- Observational study of disorders of sex development in Yaounde, Cameroon
- Letter to the Editor
- Reforming the male Tanner genital scale
- Short Communication
- The association between vitamin D levels and precocious puberty: a meta-analysis
- Case Reports
- Partial trisomy 9p and 14q microduplication in a patient with growth retardation: a case report and review of the literature
- Two different missense mutations of PEX genes in two similar patients with severe Zellweger syndrome: an argument on the genotype-phenotype correlation
- Patient report
- Marked phenotypic variable expression among brothers with duplication of Xq27.1 involving the SOX3 gene
- Case Report
- Does the risk of arterial hypertension increase in the course of triptorelin treatment?
Artikel in diesem Heft
- Frontmatter
- Original Articles
- Vitamin D status in Israeli pediatric type 1 diabetes patients: the AWeSoMe Study Group experience and literature review
- Metabolic features and changes in glucose-induced serum glucagon-like peptide-1 levels in children with hypothalamic obesity
- Assessment of intima-media thickness of the carotid artery and intraluminal diameter of the brachial artery as cardiovascular risk markers in Brazilian adolescents with overweight or obesity
- The role of LCPUFA-ω3 on the obesity-associated hyperandrogenemia of pubertal girls: secondary analysis of a randomized clinical trial
- Genetic variants of the phenylalanine hydroxylase gene in patients with phenylketonuria in the northeast of Iran
- Oral health status of children with phenylketonuria
- Birth weight related blood concentrations of the neurotransmission amino acids glutamine plus glutamate, phenylalanine and tyrosine in full-term breastfed infants perinatally
- Hyperthyrotropinemia is common in preterm infants who are born small for gestational age
- Radioactive iodine therapy for pediatric Graves’ disease: a single-center experience over a 10-year period
- The decision-making levels of urine tetrasaccharide for the diagnosis of Pompe disease in the Turkish population
- A questionnaire study on sleep disturbances associated with Prader-Willi syndrome
- Body size measurements, digit ratio (2D:4D) and oestrogen and progesterone receptors’ expressions in juvenile gigantomastia
- The effect of celiac disease and gluten-free diet on pubertal development: a two-center study
- Observational study of disorders of sex development in Yaounde, Cameroon
- Letter to the Editor
- Reforming the male Tanner genital scale
- Short Communication
- The association between vitamin D levels and precocious puberty: a meta-analysis
- Case Reports
- Partial trisomy 9p and 14q microduplication in a patient with growth retardation: a case report and review of the literature
- Two different missense mutations of PEX genes in two similar patients with severe Zellweger syndrome: an argument on the genotype-phenotype correlation
- Patient report
- Marked phenotypic variable expression among brothers with duplication of Xq27.1 involving the SOX3 gene
- Case Report
- Does the risk of arterial hypertension increase in the course of triptorelin treatment?
