Functional and structural characterization of novel mutations and genotype–phenotype correlation in 51 phenylalanine hydroxylase deficient families from Southern Italy

Daniele, Aurora; Scala, Iris; Cardillo, Giuseppe; Pennino, Cinzia; Ungaro, Carla; Sibilio, Michelina; Parenti, Giancarlo; Esposito, Luciana; Zagari, Adriana; Andria, Generoso; Salvatore, Francesco

doi:10.1111/j.1742-4658.2009.06940.x

Cited by 29 publications

(15 citation statements)

References 43 publications

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“…Although this is not always the case, similarly to other studies, we usually found a correlation between genotype and response to BH4; some studies establish a 76% correlation, others deem there to be good correlations, particularly in homozygotes, for nonresponsive mutations (Daniele et al 2009;Desviat et al 2004;Trefz et al 2009b;Zurfl€ uh et al 2008). …”

Section: Discussionsupporting

confidence: 87%

Long-Term Pharmacological Management of Phenylketonuria, Including Patients Below the Age of 4 Years

Couce¹,

Bóveda²,

Valerio³

et al. 2011

JIMD Reports

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BH4 therapy is an advancement in the treatment of phenylketonuria, reducing blood phenylalanine (phe) levels and increasing tolerance to natural proteins of responding patients. We report the results of 16 patients undergoing long-term BH4 treatment. Responding patients to BH4 was usually based on 24-h loading tests; a !30% decrease in blood phe was considered a positive response. Weekly loading made it possible to identify an additional "slow responder." The 16 responders constitute 24.6% of patients who completed the trial (87.5% of responders in mild hyperphenylalaninemia, 38.1% in mild PKU, and 2.8% in classical PKU).Mean dose of BH4 used was 9.75 AE 0.9 mg/kg per day, during a mean of 62 months. Age at treatment start was below 4 years in seven patients; five of which begun treatment during their first month since birth. All but one patient showed good treatment compliance; six continue on BH4 monotherapy without dietary phe restriction; six showed an increase in phe tolerance of 24-55%; and in the five patients who received treatment since the neonatal period an increase in phe tolerance following the phase of maximum growth has persisted. None of the patients showed side effects except one whom vomiting at the beginning of the treatment.Testing at the time of diagnosis in the neonatal period is very appropriate, and if there is a positive response, the patient can be treated with BH4 from onset with the advantage of being able to continue breast-feeding.

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Section: Discussionsupporting

confidence: 87%

Long-Term Pharmacological Management of Phenylketonuria, Including Patients Below the Age of 4 Years

Couce¹,

Bóveda²,

Valerio³

et al. 2011

JIMD Reports

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“…The lack of standardized methods for the classification of HPA phenotypes can complicate the interpretation of genotype-phenotype correlations (Daniele et al, 2009). In this study, we used pre-treatment plasma Phe levels for phenotypic classification.…”

Section: Discussionmentioning

confidence: 99%

A preliminary mutation analysis of phenylketonuria in southwest Iran

Ajami¹,

Nezhad²,

Foroughmand³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. Phenylketonuria (PKU) is a heterogeneous and autosomal recessive metabolic disorder that is mainly caused by mutations in the hepatic phenylalanine hydroxylase (PAH) gene. This study was designed to identify PAH mutations within exons 6, 7, and 10-12 in PKU patients from southwest Iran. Forty Iranian patients with clinical and biochemically confirmed PKU were enrolled. The exons were sequenced directly and 13 different mutations were identified including I224T, S231P, R176X, c.592_613del22, R243X, R252W, R261Q, Y356X, V388M, IVS10-11G>A, IVS11+1G>C, IVS11-2A>G, and Q375R, which were associated with 23 genotypes. A novel sequence variant, Q375R (c.1124A>G), was detected in exon 11. In one patient, a typical genotype with more than two mutations (R243X/S231P/ S231P) was found. Seven different polymorphisms and three new variants were also detected in intron regions of PAH. A high mutation spectrum was predicted in the southwestern region of Iran due to its ethnic heterogeneity, especially the Khuzestan Province. The detection PAH mutations in southwest Iran of 13 different mutations, corresponding to a mutation detection rate of 53.75%, confirmed this phenomenon.

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“…Much research has been directed at determining which genotypes are likely to respond to BH 4 , with varying results (e.g. (11, 39, 52, 54–58)).…”

Section: Bh4 Acting As a Pharmacological Chaperonementioning

confidence: 99%

“…100 – 200 μM). It is also interesting that patients expressing the L48S and/or I65T variants are reported as having highly variable responses to BH 4 therapy (54, 58, 65). …”

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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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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Functional and structural characterization of novel mutations and genotype–phenotype correlation in 51 phenylalanine hydroxylase deficient families from Southern Italy

Cited by 29 publications

References 43 publications

Long-Term Pharmacological Management of Phenylketonuria, Including Patients Below the Age of 4 Years

Long-Term Pharmacological Management of Phenylketonuria, Including Patients Below the Age of 4 Years

A preliminary mutation analysis of phenylketonuria in southwest Iran

New protein structures provide an updated understanding of phenylketonuria

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