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. 2021 Oct 23;12(11):1676.
doi: 10.3390/genes12111676.

An Updated PAH Mutational Spectrum of Phenylketonuria in Mexican Patients Attending a Single Center: Biochemical, Clinical-Genotyping Correlations

Marcela Vela-Amieva  1 , Miguel Angel Alcántara-Ortigoza  2 , Isabel Ibarra-González  3 , Ariadna González-Del Angel  2 , Liliana Fernández-Hernández  2 , Sara Guillén-López  1 , Lizbeth López-Mejía  1 , Rosa Itzel Carrillo-Nieto  1 , Leticia Belmont-Martínez  1 , Cynthia Fernández-Lainez  1
Affiliations

An Updated PAH Mutational Spectrum of Phenylketonuria in Mexican Patients Attending a Single Center: Biochemical, Clinical-Genotyping Correlations

Marcela Vela-Amieva et al. Genes (Basel). .

Abstract

Establishing the genotypes of patients with hyperphenylalaninemia (HPA)/phenylketonuria (PKU, MIM#261600) has been considered a cornerstone for rational medical management. However, knowledge of the phenylalanine hydroxylase gene (PAH) mutational spectrum in Latin American populations is still limited. Herein, we aim to update the mutational PAH spectrum in the largest cohort of HPA/PKU Mexican patients (N = 124) reported to date. The biallelic PAH genotype was investigated by Sanger automated sequencing, and genotypes were correlated with documented biochemical phenotypes and theoretical tetrahydrobiopterin (BH4) responsiveness. Patients were biochemically classified as having classic PKU (50%, 62/124), mild PKU (20.2%, 25/124) and mild HPA (29.8%, 37/124). Furthermore, 78.2% of the included patients (97/124) were identified by newborn screening. A total of 60 different pathogenic variants were identified, including three novel ones (c. 23del, c. 625_626insC and c. 1315 + 5_1315 + 6insGTGTAACAG), the main categories being missense changes (58%, 35/60) and those affecting the catalytic domain (56.6%, 34/60), and c. 60 + 5G > T was the most frequent variant (14.5%, 36/248) mainly restricted (69.2%) to patients from the central and western parts of Mexico. These 60 types of variants constituted 100 different biallelic PAH genotypes, with the predominance of compound-heterozygous ones (96/124, 77%). The expected BH4 responsiveness based on the PAH genotype was estimated in 52% of patients (65/124), mainly due to the p. (Val388Met) (rs62516101) allele. Instead, our study identified 27 null variants with an allelic phenotype value of zero, with a predominance of c. 60 + 5G > T, which predicts the absence of BH4 responsiveness. An identical genotype reported in BIOPKUdb was found in 92/124 (74%) of our patients, leading to a genotype-phenotype concordance in 80/92 (86.9%) of them. The high number of variants found confirms the heterogeneous and complex mutational landscape of HPA/PKU in Mexico.

Keywords: Latin America; PAH molecular spectrum; newborn screening; phenylalanine; phenylketonuria; rare diseases; tetrahydrobiopterin.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Workflow scheme for inclusion in the present study of 124 patients bearing PAH biallelic genotypes. The biochemical characteristics of the four identified patients bearing monoallelic PAH genotypes are shown. The 14 patients with normal PAH genotypes are currently under study for BH4 defects. Abbreviations: HPA: hyperphenylalaninemia; PAH: phenylalanine hydroxylase gene; Phe: phenylalanine; Tyr: tyrosine; mPKU: mild phenylketonuria; MHP: mild hyperphenylalaninemia.
Figure 2
Figure 2
Main categories of the 60 types of different pathogenic variants identified among the 124 unrelated Mexican patients bearing a diagnostic biallelic PAH genotype. (a) Classification by predicted pathogenic effect of the variant. (b) Classification by affected domain. Frameshift, start-loss, splicing defects and non-sense were considered as null alleles. N = number of alleles/total of alleles (60).
Figure 3
Figure 3
PAH gene diagram showing the localization of the 60 types of variants found in the present study. Novel variants are in red bold type. The most common pathogenic c. 60 + 5G > T splicing variant (14.5% of the PAH alleles) is highlighted in blue bold type. The apparently synonymous variants, p. (Gln304=) and p. (Arg400=), disrupt an exon splicing enhancer element, leading to a splicing defect (BIOPKUdb). E1-E13 diagrammatic representations of exons 1 to 13 of PAH.
Figure 4
Figure 4
Brain NMRI imaging of two CD patients diagnosed with homozygous genotype c. 60 + 5G > T, and cPKU phenotype. (A) Diffusion NMRI of one-year-old male, showing restricted diffusion in periventricular white matter and basal ganglia (arrows). Hypomyelination and brain atrophy were also observed. (B) Axial T2 FLAIR imaging of a 10-year-old female showing periventricular white matter hyperintensity (arrows).
Figure 5
Figure 5
Location of His-264 residue in PAH structure. (A) His-264 residue is located within the vicinity of the active site; (B) zoom of His-264 location that shows a distance of 7.5 Å from the catalytic PAH site; (C) illustration of resulting repulsive clashes (red hexagons) conditioned by the His residue substitution by the positively charged Arg residue. The figure was constructed with Pymol [13]. THA = 3-(2-thienyl)-L-alanine (phenylalanine analogue).
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