Mutation analysis of the phenylalanine hydroxylase gene in Azerbaijani population, a report from West Azerbaijan province of Iran

Document Type : Original Article

Authors

1 Food and Beverages Safety Research Center, Urmia University of Medical Sciences, Urmia, Iran

2 Genetics Department, Urmia University of Medical Sciences, Urmia, Iran

3 Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran

4 Neurophysiology Research Center, Urmia University of Medical Sciences, Urmia, Iran

Abstract

Objective(s):Phenylketonuria (PKU) is a genetic inborn error of phenylalanine (Phe) metabolism resulting from insufficiency in the hepatic enzyme, phenylalanine hydroxylase (PAH), which leads to elevated levels of Phe in the blood. The present study was carried out for mutation analysis of the PAH gene in West Azerbaijan province of Iran.
Materials and Methods:A total of 218 alleles from 40 PKU families were studied using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR) method.
Results:The frequencies of IVS10-11, S67P, R261Q, R252W, IVS11nt-1 g>c, R408Q, and Q232Q mutations were 28(35), 17(21.25), 15(18.75), 3(3.75), 3(3.75), 2(2.5), and 1(1.25), in cases group, and 51(23.4), 31(14.2), 27(12.4), 6(2.75), 6(2.75), 4(1.83), and 2(0.92) in total group, respectively. The mutations of R243Q, 364delG, L333F, 261X, I65T, and R408W were not detected in our samples.
Conclusion: It can be concluded that the IVS10-11 mutation has the highest frequency in the tested population. To our knowledge, this report is the first in its own kind and provides better understanding of the genetic heterogeneity, the origin and distributions of PAH mutations in West Azerbaijan province of Iran.

Keywords


1.Dworniczak B, Aulehla-Scholz C, Kalaydjieva L, Bartholome K, Grudda K, Horst J. Aberrant splicing of phenylalanine hydroxylase mRNA: the major cause for phenylketonuria in parts of southern Europe. Genomics 1991; 11:242-246.
2.Guthrie R, Susi A. A simple phenylalanine method for detecting phenylketonuria in large populations of newborn infants. Pediatrics 1963; 32:338-343.
3.Rohr FJ, Allred EN, Turner M, Simmons J, Levy HL. Use of the Guthrie bacterialinhibition assay to monitor blood phenylalanine for dietary treatment ofphenylketonuria. Screening 1996; 4:205–211.
4.Vallian S, Barahimi E, Moeini H. Phenylketonuria in Iranian population: a study in institutions for mentally retarded in Isfahan. Mutat Res 2003; 526:45-52.
5.Holmgren G, Larsson A, Palmstierna H, Alm J. The frequency of PKU and hyperphenylalaninemia in Sweden-a study in institutions for the mentally retarded as well as in neonates. Clin Genet 1976; 10:313-318.
6.DiLella AG, Woo SL. Molecular basis of phenylketonuria and its clinical applications. Mol Biol Med 1987; 4:183-192.
7.Scriver CR, Kaufman S. Hyperphenylalaninemia: phenylalanine hydroxylase deficiency. New York, NY: McGraw-Hill; 2001.
8.Fazeli Z, Vallian S. Phenylketonuria from genetics to clinics: An Iranian prospect. Iran J Biotechnol 2011; 9:163-172.
9.Derenko M, Malyarchuk B, Bahmanimehr A, Denisova G, Perkova M, Farjadian S, Yepiskoposyan L. Complete mitochondrial DNA diversity in Iranians. PLoS One 2013; 8:e80673.
10.Koochmeshgi J, Bagheri A, Hosseini-Mazinani SM. Incidence of phenylketonuria in Iran estimated from consanguineous marriages. J Inherit Metab Dis 2002; 25:80-81.
11.Khemir S, Siala H, Taieb SH, Cherif W, Azzouz H, Kéfi R, et al. Screening of three Mediterranean phenylketonuria mutations in Tunisian families. J  Genet 2012; 91:91-94.
12.Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988; 16:1215.
13.Zschocke J, Graham CA, Carson DJ, Nevin NC. Phenylketonuria mutation analysis in Northern Ireland: a rapid stepwise approach. Am J Hum Genet 1995; 57:1311-1317.
14.Guldberg P, Romano V, Ceratto N, Bosco P, Ciuna M, Indelicato A, et al. Mutational spectrum of phenylalanine hydroxylase deficiency in Sicily: implications for diagnosis of hyperphenylalaninemia in southern Europe. Hum Mol Genet 1993; 2:1703-1707.
15.Gable M, Williams M, Stephenson A, Okano Y, Ring S, Hurtubise M, et al.  Comparative multiplex dosage analysis detects whole exon deletions at the phenylalanine hydroxylase locus. Hum Mutat 2003; 21:379-386.
16.Bonyadi M, Omrani O, Moghanjoghi SM, Shiva S. Mutations of the phenylalanine hydroxylase gene in Iranian Azeri Turkish patients with phenylketonuria. Genet Test Mol Biomarkers 2010; 14:233-235.
17.Zare-Karizi Sh, Hosseini-Mazinani SM, Khazaei-Koohpar Z, Seifati SM, Shahsavan-Behboodi B, Akbari MT, et al. Mutation spectrum of phenylketonuria in Iranian population. Mol Genet Metab 2011; 102:29-32.
18.Desviat LR, Perez B, Gutierrez E, Sanchez A, Barrios B, Ugarte M. Molecular basis of phenylketonuria in Cuba. Hum Mutat 2001; 18:252-255.
19.Acosta AX, Silva WA, Carvalho TM, Zago MA. Ten novel mutations in the phenylalanine hydroxylase gene (PAH) observed in Brazilian patients with phenylketonuria. Hum Mutat 2001; 17:77.
20.Ozgüç M, Ozalp I, Coşkun T, Yilmaz E, Erdem H, Ayter S. Mutation analysis in Turkish phenylketo-nuria patients. J Med Genet 1993; 30:129-130.
21.Effat LK, Essawi ML, Abd El Hamid MS, Hawari N, Gad YZ. Screening for six Mediterranean mutations in 90 Egyptian patients with phenylketonuria. Bratisl Lek Listy 2008; 109:17-19.
22.Berthelon M, Caillaud C, Rey F, Labrune P, Melle D, Feingold J, et al. Spectrum of phenylketonuria mutations in Western Europe and North Africa, and their relation to polymorphic DNA haplotypes at the phenylalanine hydroxylase locus. Hum Genet 1991; 86: 355-358.
23.Perez B, Desviat LR, Die M, Ugarte M. Mutation analysis of phenylketonuria in Spain: prevalence of two Mediterranean mutations. Hum Genet 1992; 89:341-342.