Evaluation of PAH Gene Mutations in Exonic and Exon-Intron Junction Regions in Families with Classical PKU in Basrah, Iraq

Abstract

Phenylketonuria (PKU) is a rare inherited disorder that affects how the body processes the amino acid phenylalanine (Phe), a component found in many protein-rich foods. The condition stems from a deficiency or complete inactivity of the enzyme phenylalanine hydroxylase (PAH), which normally converts Phe into another amino acid, tyrosine. Without sufficient PAH activity, Phe accumulates in the body to toxic levels, leading to serious and often irreversible damage to the brain and nervous system. This can result in intellectual disabilities and other neurological complications if not managed early. In an effort to better understand the genetic mutations associated with PKU in the local population, a descriptive cross-sectional study was conducted involving 15 patients from Basrah, Iraq. Blood samples were taken from each participant, and DNA was extracted for analysis. The study focused on sequencing both the exons and introns (regions within and surrounding the coding areas) of the PAH gene using Sanger sequencing, which remains a gold-standard method for detecting point mutations. The analysis revealed several recurring mutations. The most frequent was c.782G>A located in exon 7, found in 40% of the patients. This was followed by c.1066-11G>A in intron 10 (33.3%), c.168+5G>C in intron 2 (13.5%), and c.926C>A in exon 9 (13.5%). Each of these mutations could potentially interfere with the normal function of the PAH enzyme, contributing to the metabolic dysfunction observed in these patients. The findings highlight the genetic diversity of PKU mutations even within a relatively small sample group. This suggests a need for broader genetic studies across Iraq’s different ethnic groups to further explore the relationship between specific genetic mutations and clinical outcomes. Such research could be crucial in refining approaches to early diagnosis, treatment, and genetic counseling for families affected by PKU.