In vitro residual activity of phenylalanine hydroxylase variants and correlation with metabolic phenotypes in PKU

Trunzo, Roberta; Santacroce, Rosa; Shen, Nan; Jung-Klawitter, Sabine; Leccese, Angelica; Girolamo, Giuseppe De; Margaglione, Maurizio; Blau, Nenad

doi:10.1016/j.gene.2016.09.015

Cited by 16 publications

(19 citation statements)

References 22 publications

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“…A high degree of discordance (51.7%) was noticed in genotype‐phenotype correlations assessed by the arbitrary assigned values (AV) phenotype predictive system of Guldberg et al. (), modified by data from other researchers (Pey et al., ; Trunzo et al., ), and, for some mutations, by our own assessment. Guldberg et al.…”

Section: Discussionmentioning

confidence: 67%

“…Comparison of the inverse of pretreatment phenylalanine (Phe) levels (mg/dl) with the predicted phenylalanine hydroxylase (PAH) enzyme activity for a total of 81 patients for which mutant PAH residual activity (PRA) for both alleles and pretreatment Phe levels were both known. Mean PRA for each genotype was established by data in BIOPKU database and previously published articles (Aldamiz‐Echevarria et al., ; Eisensmith et al., ; Guldberg et al., ; Jeannesson‐Thivisol et al., ; Pey et al., ; Trunzo et al., ). A significant correlation ( t = 4.79, p < 0.0001) was found by linear regression analysis: y = 0.0007 x + 0.0379, R 2 = 0.225…”

Section: Resultsmentioning

confidence: 99%

“…All patients were completely genotyped formerly by our group (Vieira Neto et al, 2018). Table 1 presents the mutations found in these patients and their predicted PAH residual activities (null mutations pointed out) as indicated by Himmelreich et al (2018), from previous publications (Aldamiz-Echevarria et al, 2016;Eisensmith et al, 1996;Guldberg et al, 1998;Jeannesson-Thivisol et al, 2015;Pey et al, 2003;Trunzo et al, 2016) or judged as null in the case of nonsense mutations, frameshift and large deletions whose PAH residual activities were not formerly reported.…”

Section: Genotype Analysismentioning

confidence: 98%

“…n Zurfluh et al (2008) consider this mutation as of uncertain BH 4 responsiveness but data from nine patients in the BIOPKU database, two homozygotes and seven compound heterozygotes with a null mutation, showed they were BH 4 nonresponsive, although two compound heterozygotes with a null mutation were slow responders. o Data from Trunzo et al (2016). p Described by our group (Vieira Neto et al, 2018).…”

Section: "Functionally Hemizygous" Genetic Combinationsmentioning

confidence: 99%

“…Genotype-phenotype correlation studies in PKU/MHP traditionally employ predicted PAH residual activity (PRA) of each mutation provided by in vitro experiments or by the analysis of its effect on protein structure (Danecka et al, 2015;Gjetting, Petersen, Guldberg, & Guttler, 2001;Pey, Desviat, Gamez, Ugarte, & Perez, 2003;Pey, Stricher, Serrano, & Martinez, 2007;Trunzo et al, 2016). Another approach for investigating genotype-phenotype correlations is the analysis both of homoallelic mutant genotypes and of the so-called "functionally hemizygous" heteroallelic genotypes, that is, patients who carry a functionally null mutation on one of their alleles and a missense or an in-frame small deletion on the other (Kayaalp et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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Genotype‐phenotype correlations and BH₄ estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil

Neto

Laranjeira

Quelhas

et al. 2019

Molec Gen & Gen Med

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Background Genetic heterogeneity and compound heterozygosis give rise to a continuous spectrum of phenylalanine hydroxylase deficiency and metabolic phenotypes in phenylketonuria (PKU). The most used parameters for evaluating phenotype in PKU are pretreatment phenylalanine (Phe) levels, tolerance for dietary Phe, and Phe overloading test. Phenotype can vary from a “classic” (severe) form to mild hyperphenylalaninemia, which does not require dietary treatment. A subset of patients is responsive to treatment by the cofactor tetrahydrobiopterin (BH 4 ). Genotypes of PKU patients from Rio de Janeiro, Brazil, were compared to predicted and observed phenotypes. Genotype‐based estimations of responsiveness to BH 4 were also conducted. Methods Phenotype was defined by pretreatment Phe levels. A standard prediction system based on arbitrary assigned values was employed to measure genotype‐phenotype concordance. Patients were also estimated as BH 4 ‐responders according to the responsiveness previously reported for their mutations and genotypes. Results A 48.3% concordance rate between genotype‐predicted and observed phenotypes was found. When the predicted phenotypes included those reported at the BIOPKU database, the concordance rate reached 77%. A total of 18 genotypes from 30 patients (29.4%) were estimated as of potential or probable BH 4 responsiveness. Inconsistencies were observed in genotypic combinations including the common “moderate” mutations p.R261Q, p.V388M, and p.I65T and the mild mutations p.L48S, p.R68S, and p.L249F. Conclusion The high discordance rate between genotype‐predicted and observed metabolic phenotypes in this study seems to be due partially to the high frequency of the so‐called “moderate” common mutations, p.R261Q, p.V388M, and p.I65T, which are reported to be associated to erratic or more severe than expected metabolic phenotypes. Although our results of BH 4 estimated responsiveness must be regarded as tentative, it should be emphasized that genotyping and genotype‐phenotype association studies are important in selecting patients to be offered a BH 4 overload test, especially in low‐resource settings like Brazil.

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Section: Discussionmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Section: Genotype Analysismentioning

confidence: 98%

Section: "Functionally Hemizygous" Genetic Combinationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Genotype‐phenotype correlations and BH₄ estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil

Neto

Laranjeira

Quelhas

et al. 2019

Molec Gen & Gen Med

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Unique aspects of sequence variant interpretation for inborn errors of metabolism (IEM): The ClinGen IEM Working Group and the Phenylalanine Hydroxylase Gene

et al. 2018

Self Cite

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The ClinGen Inborn Errors of Metabolism Working Group was tasked with creating a comprehensive, standardized knowledge base of genes and variants for metabolic diseases. Phenylalanine hydroxylase (PAH) deficiency was chosen to pilot development of the Working Group’s standards and guidelines. A PAH variant curation expert panel (VCEP) was created to facilitate this process. Following ACMG-AMP variant interpretation guidelines, we present the development of these standards in the context of PAH variant curation and interpretation. Existing ACMG-AMP rules were adjusted based on disease (6) or strength (5) or both (2). Disease adjustments include allele frequency thresholds, functional assay thresholds, and phenotype-specific guidelines. Our validation of PAH-specific variant interpretation guidelines are presented using 85 variants. The PAH VCEP interpretations were concordant with existing interpretations in ClinVar for 69 variants (81%). Development of biocurator tools and standards are also described. Using the PAH-specific ACMG-AMP guidelines 714 PAH variants have been curated and will be submitted to ClinVar. We also discuss strategies and challenges in applying ACMG-AMP guidelines to autosomal recessive metabolic disease, and the curation of variants in these genes.

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Current trends in site and target specific delivery of nanomedicine for gene therapy

Muthuraman

Mehdi

Rishitha

2019

Nanoparticles in Pharmacotherapy

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In vitro residual activity of phenylalanine hydroxylase variants and correlation with metabolic phenotypes in PKU

Cited by 16 publications

References 22 publications

Genotype‐phenotype correlations and BH₄ estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil

Genotype‐phenotype correlations and BH₄ estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil

Unique aspects of sequence variant interpretation for inborn errors of metabolism (IEM): The ClinGen IEM Working Group and the Phenylalanine Hydroxylase Gene

Current trends in site and target specific delivery of nanomedicine for gene therapy

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In vitro residual activity of phenylalanine hydroxylase variants and correlation with metabolic phenotypes in PKU

Cited by 16 publications

References 22 publications

Genotype‐phenotype correlations and BH4 estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil

Genotype‐phenotype correlations and BH4 estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil

Unique aspects of sequence variant interpretation for inborn errors of metabolism (IEM): The ClinGen IEM Working Group and the Phenylalanine Hydroxylase Gene

Current trends in site and target specific delivery of nanomedicine for gene therapy

Contact Info

Product

Resources

About

Genotype‐phenotype correlations and BH₄ estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil

Genotype‐phenotype correlations and BH₄ estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil