PAH Mutational Spectrum of Phenylketonuria in Ecuadorian Patients, Diverse Frequency, And Genotypes

Abstract:

Background: Phenylketonuria (PKU) is an autosomal recessive disease caused by mutations in the Phenylalanine Hydroxylase (PAH) gene. PKU is part of the newborn screening in many South American countries, and genotype-phenotype information is available from Brazil, Chile, and Argentina but not from Ecuador. Methods: We reviewed the medical history of Ecuadorian patients with PKU, correlated genotype-phenotype, allele frequencies, allelic phenotype value, enzyme activity, SIFT and Polyphen, and BH4 responsive alleles from the BioPKU database and modeled the protein of the newly detected genotypes. Results: The most frequent worldwide PAH variants and genotypes were not found in Ecuador. The most frequent alleles in Ecuador included p.[Arg252Trp];[Arg252Trp], p.[Ser349Pro];[Ser349Pro], and c.[441+ 5G> T];[441+ 5G> T]. p.[Arg252Trp]/c.[441+ 5G> T] genotype and p.[Ser349Pro];[Ser349Pro] homozygote were the most frequent genotypes. We reported five new genotypes and four new molecular variants not reported in the BioPKU database. Conclusion: Ecuador is a country with a mixed population because of the genetic interaction throughout history between African, European, and American genes. The low frequency of global variants and high frequency of rare suggest a dominance of unreported indigenous variants and unique genotype-phenotype in the eastern part of South America with a low frequency of European variants. This highlights the importance of developing new molecular panels for metabolic disorders to analyze and detect variants found specifically in regions of Latin America.

Año de publicación:

2023

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Fuente:

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