Mutation analysis of Phenylalanine hydroxylase gene in Iranian patients with Phenylketonuria

Abstract

Background: Phenylketonuria as the most common genetic metabolic disorder is the result of disruption of the phenylalanine hydroxylase gene. This study was carried out to explore the phenylalanine hydroxylase gene mutation status of Iranian phenylketonuria patients. Methods: Blood samples were collected from 30 patients, and hot spot areas of the phenylalanine hydroxylase gene, including exons 6, 7, 8, 11, and 12 were studied through polymerase chain reaction and sequencing techniques. Results: Eight different mutations, including 5 missense mutations, 1 splice mutation, 1 nonsense mutation, and 1 Silent/Splice mutation were detected. These mutations were R243X, R261Q, R261X, P281L, R241C, V399V, E280K, and IVS11+1G>C. V399V and R241C were reported for the first time in Iranian population. Three polymorphisms including Q232Q, V245V and L385L and 3 novel intronic variants including IVS10-15A>C, IVS6+44T>G, and IVS6+36 T>G were also detected in this study. Conclusion: The results of this study prove the heterogeneous status of phenylalanine hydroxylase gene mutations in the Iranian population, which can be useful in carrier testing and genetic counseling.

Tandem Mass Spectrometry Screening for Inborn Errors of Metabolism in Newborns and High-Risk Infants in Southern China: Disease Spectrum and Genetic Characteristics in a Chinese Population

“…The symbol "#" in superscript represents unreported, and "-" represents no mutation or not checked out. Zhang et al, 2018), the c.1222C > T mutation is the most common in the United States (Kaul et al, 1994), c.1238G > C is common in Japan (Okano et al, 2011), and IVS10-11G > A is the most common in Iran and Spain (Bueno et al, 2013;Rastegar Moghadam et al, 2018). In the present study, eight kinds of 12 mutation sites were found in the PHA gene: c.1174T > A, c.1223G > A, c.208_210del, c.611A > G, c.331C > T, c.728G > A, c.320A > G, and c.721C > T. Further, c.1223G > A was the most common PAH mutation site, accounting for 25% of all mutation types, potentially representing a hot spot mutation in this region.…”

Expanded Newborn Screening for Inborn Errors of Metabolism by Tandem Mass Spectrometry in Suzhou, China: Disease Spectrum, Prevalence, Genetic Characteristics in a Chinese Population

“…Some hotspot mutations exist in PAH gene and vary in different populations. For example, the most common PAH mutation is c.1222C > T in American (Kaul et al, 1994), IVS10-11G > A in Iranian (Zamanfar et al, 2017; Esfahani and Vallian, 2018; Rastegar Moghadam et al, 2018) and Spanish (Bueno et al, 2013; Aldámiz-Echevarría et al, 2016), c.168+5G > C in western Iranian (Alibakhshi et al, 2014), c.1238G > C in Japanese (Okano et al, 2011; Dateki et al, 2016), c.728G > A in Chinese (Zhou et al, 2012; Li et al, 2015; Zhang et al, 2018), c.781C > T in Karachays (Gundorova et al, 2018), c.1068C > A and c.728G > A in south Korean (Lee et al, 2008), c.1162G > A in Brazilian (Vieira Neto et al, 2018), c.782G > A in Syrian (Murad et al, 2013), and c.1222C > T in Australian (Ho et al, 2014). These different hotspot mutations suggested different origins.…”

Utility of Gene Panels for the Diagnosis of Inborn Errors of Metabolism in a Metabolic Reference Center

“…This variant consists of an alteration in a conserved nucleotide at position 261, where the aromatic amino acid hydroxylase is located, in the C-terminal of the phenylalanine-4-hydroxylase protein. This variant has been associated with benign hyperphenylalaninemia and classic phenylketonuria requiring dietary treatment [51,52], and has an allelic frequency of 5.3-5.5% [53,54]. In vitro studies have shown that the c.782G > A variant alters the function of the protein and that the resulting enzyme retains a residual level of activity (6.3-11%), which may explain the moderate phenotype associated with the variant [55].…”