Phenylalanine hydroxylase deficiency in south Italy: Genotype–phenotype correlations, identification of a novel mutant PAH allele and prediction of BH4 responsiveness

Trunzo, Roberta; Santacroce, Rosa; D’Andrea, Giovanna; Longo, Vittoria; Girolamo, Giuseppe De; Dimatteo, Claudia; Leccese, Angelica; Bafunno, Valeria; Lillo, Vincenza; Papadia, Francesco; Margaglione, Maurizio

doi:10.1016/j.cca.2015.07.014

Cited by 14 publications

(10 citation statements)

References 24 publications

(26 reference statements)

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“…Since the genotype determines the activity of PAH and thus the metabolic phenotype, there is growing evidence of genotype–phenotype correlation [Trefz et al., ; Kayaalp et al., ; Benit et al., ; Jennings et al., ; Kasnauskiene et al., ; Pey et al., ; Bercovich et al., ; Daniele et al., ; Bueno et al., Polak et al., ; Reblova et al., ; Tao et al., ; Trunzo et al., ]. It has been known for about 20 years that PAH activity predicts the clinical phenotype (blood Phe) in PKU [Eisensmith and Woo, ].…”

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

confidence: 99%

Genetics of Phenylketonuria: Then and Now

2016

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

confidence: 99%

Genetics of Phenylketonuria: Then and Now

2016

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“…IVS 10-11g→a is also found to be the most common PKU mutation in several countries such as; Southern Italy (12.1%) 13 , Sicily (15%) 14 , Spain (13.8%) 15 and Portugal (14.6%) 16 . Our finding of the frequency for IVS10-11g→a mutation may suggest a selection due to the high frequency of different ethnic groups and consanguineous marriages in Çukurova region 17 .…”

Section: Discussionmentioning

confidence: 99%

“…Most common PAH mutation causing PKU is IVS 10-11g→a in the Mediterranean region, particularly in Turkey where its frequency is found to be more than 30% of PKU alleles 11 and also in a study made on patients of Turkish descent living in Germany, a similar frequency of 38% is obtained 12 . IVS 10-11g→a is also found to be the most common PKU mutation in several countries such as; Southern Italy (12.1%) 13 , Sicily (15%) 14 , Spain (13.8%) 15 and Portugal (14.6%) 16 . Our finding of the frequency for IVS10-11g→a mutation may suggest a selection due to the high frequency of different ethnic groups and consanguineous marriages in Çukurova region 17 .…”

Section: Discussionmentioning

confidence: 99%

Türk hastalarda Fenilalanin Hidroksilaz gen mutasyonlarının dizileme ve ARMS teknikleri ile incelenmesi

Lüleyap¹,

Pazarcı²,

Cömertpay³

et al. 2016

Cukurova Medical Journal (Çukurova Üniversitesi Tıp Fakültesi Dergisi)

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AbstractÖz Purpose: Phenylketonuria is an autosomal recessive deficiency of the hepatic enzyme phenylalanine hydroxylase. With this study, detection of the most frequent phenylalanine hydroxylase gene mutations in Turkish population is aimed. Material and Methods: 23 unrelated phenylketonuria patients (46 alleles) who are living in Cukurova region, Turkey were investigated.First, all exons were screened by using DHPLC method then the direct sequencing technique and ARMS methods were used to analyze mutation suspected samples. Results: IVS10-11g→a splicing mutation in 27 alleles (58.7%), R261Q mutation in 7 alleles (15.2%) and E178G, P281L, R243X, R243Q, R408W, Y386C mutations, all in a frequency of 2/46 (4.3%) is found. Conclusion:The arginine amino acid, accounting for 68.4% of changes in exon sites 7 and 12, where R243X, R243Q, R261Q and R408W mutations occur, is thought to be important for amino acid changes in phenylalanine hydroxylase gene among phenylketonuria patients in Çukurova region. Single-base mutations like IVS10-11g→a and P281L could be detected with an accuracy of 100% by the use of specifically designed primers by authors according to ARMS technique and it is relatively cheaper and requesting less technical equipment.Amaç: Fenilketonüri, hepatik bir enzim olan fenilalanin hidroksilazın otozomal resesif bozukluğu sonucu ortaya çıkan bir durumdur. Bu çalışmada, Türk popülasyonunda en sık görülen fenilalanin hidroksilaz geni mutasyonlarını belirlemek amaçlandı. Gereç ve Yöntem: Öncelikle tüm ekson bölgeleri DHPLC metodu kullanılarak tarandı. Ardından mutasyon şüphesi taşıyan örnekler sekanslama ve ARMS yöntemleri kullanılarak analiz edildi. Bulgular: IVS10-11g→a splayzing mutasyonu 27 allelde (%58,7), R261Q mutasyonu 7 allelde (%15,2) ve E178G, P281L, R243X, R243Q, R408W, Y386C mutasyonları ise 2'şer allelde (%4,3) tespit edildi. Sonuç: R243X, R243Q, R261Q ve R408W mutasyonlarının oluştuğu 7 ve 12'inci ekson bölgelerinde arginin aminoasidinin değişimi Çukurova bölgesindeki fenilketonüri hastalarında fenilalanin hidroksilaz geni mutasyonlarında önemli bir yer tutmaktadır (%68,4). IVS10-11g→a ve P281L gibi tek baz mutasyonları bizim tarafımızdan dizayn edilmiş primerler ve ARMS tekniği kullanılarak daha ucuza, daha az teknik ekipmanla ve %100 doğrulukla tespit edilebilmektedir.

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“…The most frequent missense mutations were functionally and structurally characterised in several studies many years ago (Waters 2003). However, large-scale PKU studies continuously reveal novel variants with an unknown impact on PAH enzyme function (Groselj et al 2013;Polak et al 2013;Réblová et al 2013;Trunzo et al 2015). Therefore, it is highly important to constantly update and extend these data which contribute to a better understanding of the complex PKU nature.…”

Section: Discussionmentioning

confidence: 99%

Functional and structural characterisation of 5 missense mutations of the phenylalanine hydroxylase

Pecimonova

Polák²,

Csicsay³

et al. 2017

gpb

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Phenylketonuria (PKU) and hyperphenylalaninemia (HPA) are a group of genetic disorders predominantly caused by mutations in the phenylalanine hydroxylase (PAH) gene. To date, more than 950 variants have been identified, however the pathogenic mechanism of many variants remains unknown. In this study, in silico prediction and in vitro prokaryotic and eukaryotic expression systems were used to functionally characterize five PAH missense variants (p.F233I, p.R270I, p.F331S, p.S350Y, and p.L358F) previously identified in Slovak and Czech patients. p.F233I, p.R270I, and p.S350Y were classified as deleterious mutations since they showed no specific activity in functional assay and no response to chaperone co-expression. Protein levels of these PAH variants were very low when expressed in HepG2 cells, and only p.S350Y responded to BH4 precursor overload by significant increase in PAH monomer, probably due to reduced rate of protein degradation as the result of proper protein folding. Variants p.F331S and p.L358F exerted residual enzymatic activity in vitro. While the first can be classified as probably pathogenic due to its very low protein levels in HepG2 cells, the latter is considered to be mild mutation with protein levels of approximately 17.85% compared to wt PAH. Our findings contribute to better understanding of structure and function of PAH mutated enzymes and optimal treatment of PKU patients carrying these mutations using BH4 supplementation.

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Phenylalanine hydroxylase deficiency in south Italy: Genotype–phenotype correlations, identification of a novel mutant PAH allele and prediction of BH4 responsiveness

Cited by 14 publications

References 24 publications

Genetics of Phenylketonuria: Then and Now

Genetics of Phenylketonuria: Then and Now

Türk hastalarda Fenilalanin Hidroksilaz gen mutasyonlarının dizileme ve ARMS teknikleri ile incelenmesi

Functional and structural characterisation of 5 missense mutations of the phenylalanine hydroxylase

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