Mapping the functional landscape of frequent<i>phenylalanine hydroxylase</i>(<i>PAH</i>) genotypes promotes personalised medicine in phenylketonuria

Danecka, Marta K.; Woidy, Mathias; Zschocke, Johannes; Feillet, François; Muntau, Ania C.; Gersting, Søren W.

doi:10.1136/jmedgenet-2014-102621

Cited by 38 publications

(45 citation statements)

References 40 publications

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“…Furthermore, BH 4 and Phe compete with each other to control the position of the equilibrium (Fig 4). This correlates with the observation that some individuals living with PKU are found to achieve lower Phe levels when treated with a lesser dose of BH 4 (45). The equilibrium presented in Fig 4 also suggests that it may be possible to design or discover a pharmacological chaperone that will specifically bind to and stabilize A-PAH regardless of whether or not Phe is bound in the allosteric site .…”

Section: The Pah Structure Equilibrium and Small Molecule Stabilizationsupporting

confidence: 84%

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New protein structures provide an updated understanding of phenylketonuria

Jaffe

2017

Molecular Genetics and Metabolism

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Phenylketonuria (PKU) and less severe hyperphenylalaninemia (HPA) constitute the most common inborn error of amino acid metabolism, and is most often caused by defects in phenylalanine hydroxylase (PAH) function resulting in accumulation of Phe to neurotoxic levels. Despite the success of dietary intervention in preventing permanent neurological damage, individuals living with PKU clamor for additional non-dietary therapies. The bulk of disease-associated mutations are PAH missense variants, which occur throughout the entire 452 amino acid human PAH protein. While some disease-associated mutations affect protein structure (e.g. truncations) and others encode catalytically dead variants, most have been viewed as defective in protein folding/stability. Here we refine this view to address how PKU-associated missense variants can perturb the equilibrium among alternate native PAH structures (resting-state PAH and activated PAH), thus shifting the tipping point of this equilibrium to a neurotoxic Phe concentration. This refined view of PKU introduces opportunities for the design or discovery of therapeutic pharmacological chaperones that can help restore the tipping point to healthy Phe levels and how such a therapeutic might work with or without the inhibitory pharmacological chaperone BH4. Dysregulation of an equilibrium of architecturally distinct native PAH structures departs from the concept of “misfolding”, provides an updated understanding of PKU, and presents an enhanced foundation for understanding genotype/phenotype relationships.

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Section: The Pah Structure Equilibrium and Small Molecule Stabilizationsupporting

confidence: 84%

“…Although sophisticated kinetic analysis are reported for L48S (e.g. (45)), direct Phe binding to the regulatory domain has not. Unfortunately published kinetic analysis on many disease associated PAH variants use intact fusion proteins and/or determine the allosteric response only at 1 mM Phe.…”

Section: The Vast Array Of Disease-associated Pah Variantsmentioning

confidence: 99%

New protein structures provide an updated understanding of phenylketonuria

Jaffe

2017

Molecular Genetics and Metabolism

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“…It has not been reported in Portugal, Spain, and Hispanic America (Desviat et al., ; Hamilton et al., ; Perez et al., ; Vela‐Amieva et al., ) (Figure b,c). It is found in Middle Eastern and Central and Eastern European PKU patients (Biglari et al., ; Danecka et al., ; Kasnauskiene, Giannattasio, Lattanzio, Cimbalistiene, & Kucinskas, ; Zschocke & Hoffmann, ; Zschocke et al., ).…”

Section: Discussionmentioning

confidence: 99%

Mutation analysis of the PAH gene in phenylketonuria patients from Rio de Janeiro, Southeast Brazil

Neto

Laranjeira

Quelhas

et al. 2018

Molec Gen & Gen Med

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BackgroundPhenylketonuria (PKU) is an autosomal recessive disease resulting from mutations in the PAH gene. Most of the patients are compound heterozygotes, and genotype is a major factor in determining the phenotypic variability of PKU. More than 1,000 variants have been described in the PAH gene. Rio de Janeiro's population has a predominance of Iberian, followed by African and Amerindian ancestries. It is expected that most PKU variants in this Brazilian state have originated in the Iberian Peninsula. However, rare European, African or pathogenic variants that are characteristic of the admixed population of the state might also be found.MethodsA total of 102 patients were included in this study. Genomic DNA was isolated from dried blood spots. Sanger sequencing was used for PAH gene variant identification. Deletions and duplications were also screened using MLPA analysis. Haplotypes were also determined.ResultsNine (8.8%) homozygous and 93 (91.2%) compound heterozygous patients were found. The spectrum included 37 causative mutations. Missense, nonsense, and splicing pathogenic variants corresponded to 63.7%, 2.9%, and 22.6% of the mutant alleles, respectively. Large (1.5%), and small deletions, inframe (5.4%) and with frameshift (3.9%), comprised the remainder. The most frequent pathogenic variants were: p.V388M (12.7%), p.R261Q (11.8%), IVS10‐11G>A (10.3%), IVS2+5G>C (6.4%), p.S349P (6.4%), p.R252W (5.4%), p.I65T (4.4%), p.T323del (4.4%), and p.P281L (3.4%). One novel variant was detected: c.934G>T (p.G312C) [rs763115697].ConclusionThe three most frequent pathogenic variants in our study (34.8% of the alleles) were also the most common in other Brazilian states, Portugal, and Spain (p.V388M, p.R261Q, IVS10‐11G>A), corroborating that the Iberian Peninsula is the major source of PAH mutations in Rio de Janeiro. Pathogenic variants that have other geographical origins, such IVS2+5G>C, p.G352Vfs*48, and IVS12+1G>A were also detected. Genetic drift and founder effect may have also played a role in the mutation spectrum we observed.

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“…Overall, BH 4 responsiveness was predicted correctly for 71% of patients. In other studies, the level of residual activity of PAH, and the concentration‐dependent manner in which Phe and BH 4 regulate the activity of PAH (the “functional landscape” of PAH mutations), were strong predictors of BH 4 responsiveness [Staudigl et al., ; Danecka et al., ]. Accordingly, information on the genotype is likely to be more useful for identifying people for a BH 4 loading test, rather than accurate prediction of their BH 4 responsiveness based on the phenotype alone [Tao et al., ].…”

Section: Now: a Closer Look At The Molecular Genetics Of Pkumentioning

confidence: 99%