Molecular basis of phenylketonuria in Cuba

Desviat, Lourdes R.; Pérez, Belén; Gutierrez, Elain; Sánchez, A.; Barrios, Bárbara; Ugarte, Magdalena

doi:10.1002/humu.1183

Cited by 6 publications

(5 citation statements)

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“…The most frequent pathogenic PAH variant of non‐Iberian origin, IVS2+5G>C (6.4%), associated with haplotype 5.9, has been previously reported as a common variant in Southeast and South Brazil (Figure a). 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: 84%

“…(), in Chile (Ch), Desviat et al. (), in Cuba (Cu), Rivera et al., ; in Portugal (P), and Perez et al., , in Spain (E).…”

Section: Resultsmentioning

confidence: 99%

“…An "X" denotes RFLP haplotype uncertainty due to the lack of EcoRI and EcoRV polymorphism assays. Santos et al (2008), in Minas Gerais, Brazil (MG), Acosta et al (2001Acosta et al ( , 2001, in São Paulo, Brazil (SP), Perez et al (1999), in Chile (Ch), Desviat et al (2001), in Cuba (Cu), Rivera et al, 2011;in Portugal (P), and Perez et al, 1997, in Spain (E -). i Haplotype 5.9 or 6.9: EcoRV RFLP assay capable of distinguishing them not done; for p.G46S settled on as 5.9 according to Zschocke and Hoffmann (1999) An interesting contribution of non-Iberian European heritage to the PKU allele diversity in our population was the pathogenic variant c.136G>A (p.G46S).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 84%

“…(), in Chile (Ch), Desviat et al. (), in Cuba (Cu), Rivera et al., ; in Portugal (P), and Perez et al., , in Spain (E).…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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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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“…We herein present a newborn female patient who was born in Mexico from migrant Cuban parents and presented mild HPA conditioned by a previously unreported compound heterozygous PAH genotype involving two variants previously not described in the Mexican population [14]. While the p.(Tyr77His) variant had not been previously reported in the Cuban population, the "Celtic" or c.1222C>T or p.(Arg408Trp) variant was described with an allelic frequency of 5.3% in a Cuban cohort [29]. The two variants were previously registered in BioPKUdb [12], but this is the first description of the HPA phenotype conditioned by this compound heterozygous genotype.…”

Section: Discussionmentioning

confidence: 75%

In Silico Structural Protein Evaluation of the Phenylalanine Hydroxylase p.(Tyr77His) Variant Associated with Benign Hyperphenylalaninemia as Identified through Mexican Newborn Screening

Vela-Amieva,

Alcántara-Ortigoza,

González-del Angel

et al. 2023

Children

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Hyperphenylalaninemia (HPA), which includes phenylketonuria (PKU), is a genetic autosomal recessive disorder arising from a deficiency in the enzyme named phenylalanine hydroxylase (PAH). Affected patients can experience severe and irreversible neurological impairments when phenylalanine (Phe) blood concentration exceeds 360 μmol/L (6 mg/dL). Here, we describe a female HPA patient who was born in Mexico to Cuban non-consanguineous parents and identified by newborn screening, and who bears the previously unreported PAH NM_000277.3(PAH):c.[229T>C];[1222C>T] or p.[Tyr77His];[Arg408Trp] genotype. At diagnosis, the patient showed a Phe blood level of 321 μmol/L (5.3 mg/dL), indicative of mild HPA. Neither of the PAH variants found in this patient had been previously reported in the mutational PAH spectrum of the Mexican population. The c.229T>C or p.(Tyr77His) PAH variant was previously related to mild HPA in the Swedish population. Our in silico structural analysis and molecular docking showed that mutated His 77 residue is located in the allosteric site of PAH at the interface of the two monomers. The PDBsum in silico tool predicted that this variant would cause minimal structural disturbance of the protein interface in the presence of Phe at the allosteric site. Docking studies revealed that these structural changes might be attenuated by the allosteric effect of Phe. Given the classic PKU phenotype conditioned by the “Celtic” or c.[1222C>T] or p.(Arg408Trp) PAH variant, which is the second variant in this patient, we propose that p.(Tyr77His) has a hypomorphic feature that could explain her mild HPA phenotype. Our results show the importance of following up on cases detected by NBS and the value of genetic studies and in silico tools that aid in the establishment of correct therapeutic strategies.

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“…R243Q is a common mutation in the Southeast Asia countries. [15] R176X has previously been reported as the second major PKU-causing mutation in Moroccan[18] and in relatively frequencies in Cuban[19] and Egyptian[20] populations. The frequencies of these mutations in Iranian population is <2%.…”

Section: Discussionmentioning

confidence: 99%

Molecular analysis of exons 6 and 7 of phenylalanine hydroxylase gene mutations in Phenylketonuria patients in Western Iran

et al. 2012

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BACKGROUND:Phenylketonuria (PKU) is an inborn error of amino acid metabolism that results from a deficiency of phenylalanine hydroxylase (PAH). According to PAH database, exons 6 and 7 and their flanking introns of PAH gene contain the greatest number of mutant alleles. Therefore, as a preliminary study, nucleotide sequence analysis of exons 6 and 7 of the PAH gene has been performed in 25 PKU patients whose ancestors lived in Kermanshah province of Iran. To date, there has been no mutation data describing the genotypes of the PKU disease in this Kurdish ethnic region background.MATERIALS AND METHODS:Twenty-five patients (aged between 2 and 23 years) participated in this study. The DNA fragments containing two exons of the PAH gene [6 and 7] and their exon-flanking intronic sequences were amplified and sequenced.RESULTS:The total of detected mutations were R261X (8%), R176X (4%), R243Q (4%), R243X (2%) and R261Q (2%), as they accounted for 20% of all mutant alleles in this study. The identified polymorphisms are: IVS5 -54 G > A (22%), Q232Q (8%) and V245V (4%). All of the detected mutations in this study are related to CpG dinucleotides in the PAH gene sequence.CONCLUSION:The frequency of R261X, the most common mutation in our study, in Iranian population is <5%. Furthermore, there is no report of detection of R176X and R243Q in Isfahan and Azeri Turkish populations. These findings confirm the common Mediterranean mutations in this local population, although with more or lower frequencies than those reported in other related studies in Iran. Therefore, it may be necessary to study the PAH gene mutations in other provinces of Iran separately.

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Molecular basis of phenylketonuria in Cuba

Cited by 6 publications

References 2 publications

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

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

In Silico Structural Protein Evaluation of the Phenylalanine Hydroxylase p.(Tyr77His) Variant Associated with Benign Hyperphenylalaninemia as Identified through Mexican Newborn Screening

Molecular analysis of exons 6 and 7 of phenylalanine hydroxylase gene mutations in Phenylketonuria patients in Western Iran

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