Investigation of Polymorphic SNP Markers Linked to the QDPR Gene

Subject: Hyperphenylalaninemia (HPA) is a group of hereditary disorders characterized by an increased accumulation of phenylalanine in the blood and other tissues (phenylalanine concentration above ۲۳۱ μmol/L). This group of inherited disorders is primarily caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH) or its essential cofactor, tetrahydrobiopterin (BH۵). Non-classical phenylketonuria is an inborn error of metabolism resulting from a deficiency of the cofactor tetrahydrobiopterin (BH۵). Tetrahydrobiopterin deficiency can result from defects in enzymes involved in BH۵ biosynthesis, including guanosine ۶’-triphosphate cyclohydrolase I (GTPCH) and ۷-pyruvyltetrahydrobiopterin synthetase (PTPS), or by defects in enzymes involved in BH۵ recycling, including dihydropteridine reductase (DHPR) and pterin-۵-alpha-carbinolamine dehydratase (PCD). One of the genes involved in BH۵ regeneration is the QDPR gene at position ۵p۲۶.۴۳, which encodes the enzyme dihydropteridine reductase (DHPR). Defects in the QDPR gene lead to a deficiency of dihydropteridine reductase, which is the second most common cause of tetrahydrobiopterin deficiency. DHPR deficiency (OMIM ۳۷۲۷۴۱) is inherited in an autosomal recessive manner and presents with symptoms such as intellectual disability, motor impairment, myoclonic seizures, microcephaly, febrile seizures, truncal hypertonia with limb hypertonia, defective folate metabolism and potentially fatal outcomes due to neurotransmitter dysfunction. Due to the challenges posed by non-classical phenylketonuria and the lack of a definitive treatment for this disorder, prenatal genetic diagnosis is currently the only method to prevent the occurrence of the disorder in couples who are carriers of mutations in the QDPR gene. In these cases, linkage analysis of markers near the QDPR gene can serve as a confirmatory method for the results obtained from DNA sequencing and direct examination of the genetic alterations responsible for the disorder. Genetic markers are specific variations in DNA sequences that are located at defined positions on chromosomes. These polymorphisms can help to identify and differentiate individuals or populations and are commonly utilized in genetic and medical research. The most significant genetic markers include short tandem repeats (STRs), variable number tandem repeats (VNTRs), and single nucleotide polymorphisms (SNPs). The aim of this study was to identify polymorphic SNP markers associated with the QDPR gene. Research Method: In this study, to identify the SNP markers with the highest heterozygosity, we first determined the QDPR gene region in humans using the NCBI Gene database, based on the human genome assembly (GRCh ۴۳.p۲۵). After identifying the exact gene region, we defined one megabase upstream and one megabase downstream of the gene. To determine the upstream region of the QDPR gene, we subtracted one million from the starting nucleotide position; for the downstream region, we added one million to the ending nucleotide position. SNP markers for the internal, upstream, and downstream regions of the QDPR gene were obtained separately using the UCSC website table browser, and the data were entered into three Excel files. Three markers with the highest Minor Allele Frequencies (MAFs) were selected for the upstream and downstream regions of the gene. For the internal region of the QDPR gene, ten markers with the highest MAF were extracted from the UCSC site, and ten markers with the highest allele frequency were extracted from the Iranome database. The markers obtained from these two databases were then compared with each other. Findings and Conclusion: The range from ۲۹,۵۳۷,۴۷۶ to ۲۹,۶۲۳,۱۷۱ was identified as the QDPR gene region in humans. Markers rs۲۵۷۷۹۶۱, rs۳۳۳۲۶۷, and rs۲۵۹۳۳۴۱۵۷, with MAFs of ۱.۵۷۷۳, ۱.۵۷۷۱۱۳, and ۱.۵۷۳۷۱۳, respectively, were identified as SNP markers with the highest MAF upstream of the QDPR gene.

کلیدواژه ها:

Hyperphenylalaninemia ، QDPR gene ، polymorphic SNP markers ، tetrahydrobiopterin deficiency ، genetic markers ، single nucleotide polymorphisms ، NCBI Gene database ، UCSC website ، Minor Allele Frequencies ، Iranome database