PKU in Minas Gerais State, Brazil: Mutation Analysis

Santos, Luciana Lara dos; Castro-Magalhães, M.; Fonseca, C. G.; Starling, Ana Lúcia Pimenta; Januário, José Nélio; Aguiar, Marcos José Burle de; Carvalho, Maria Raquel Santos

doi:10.1111/j.1469-1809.2008.00476.x

Cited by 16 publications

(29 citation statements)

References 34 publications

(36 reference statements)

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“…Kinetic studies of the mutant protein with the V388M mutation showed reduced affinity of the enzyme for L-Phe and tetrahydrobiopterin (Leandro et al, 2000). This mutation is relatively common in Brazil, Portugal, and Spain (Santos et al, 2006). The Q375R mutation is a new sequence variant that is reported in the present study for the first time, and was entered into the PAH and HGMD databases.…”

Section: Discussionmentioning

confidence: 95%

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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Section: Discussionmentioning

confidence: 95%

A preliminary mutation analysis of phenylketonuria in southwest Iran

Ajami¹,

Nezhad²,

Foroughmand³

et al. 2013

Genet. Mol. Res.

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“… Data were quoted from Santos et al. (), in Minas Gerais, Brazil (MG), Acosta et al. (, ), in São Paulo, Brazil (SP), Perez et al.…”

Section: Resultsmentioning

confidence: 99%

“…Approximately 6‐9 different alleles account for the majority of mutant chromosomes described in previous PKU population genetics studies done in Latin America – Brazil (Acosta, Silva, Carvalho, Gomes, & Zago, ; Santana da Silva et al., ; Santos et al., ), Chile (Hamilton et al., ), and Mexico (Vela‐Amieva et al., ), and the Iberian Peninsula (Aldamiz‐Echevarria et al., ; Couce et al., ; Rivera et al., ); the remainder are minor, rare, and even private disease‐causing alleles.…”

Section: Introductionmentioning

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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“…Genomic DNA isolation and mutation analysis was done previously by PCR and RFLP or based on single-strand conformation polymorphism and sequencing (Santos et al, 2006(Santos et al, , 2008.…”

Section: Genotypingmentioning

confidence: 99%

“…In Minas Gerais State, in southeastern Brazil, nine mutations account for 80% of the PKU alleles (Santos et al, 2006(Santos et al, , 2008, which facilitates investigation of their phenotypic effect. Some of the mutations that are common in Minas Gerais, such as V388M, IVS2+5G>A, and IVS2+5G>C, are little known elsewhere.…”

Section: Introductionmentioning

confidence: 99%

Variations in genotype-phenotype correlations in phenylketonuria patients

Santos

Fonseca²,

Starling

et al. 2010

Genet. Mol. Res.

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ABSTRACT. Phenylalanine hydroxylase deficiency is a trait inherited in an autosomal recessive pattern; the associated phenotype varies considerably. This variation is mainly due to the considerable allelic heterogeneity in the phenylalanine hydroxylase enzyme locus. We examined the genotype-phenotype correlation in 54 phenylketonuria (PKU) patients from Minas Gerais, Brazil. Two systems were used. The first was a phenotype prediction system based on arbitrary values (AV) attributed to each mutation and the second was a correlation analysis. An AV was assigned to each mutation: AV = 1 for classical PKU mutation; AV = 2 for moderate PKU mutation; AV = 4 for mild PKU mutation, and AV = 8 for non-PKU hyperphenylalaninemia mutation. The observed phenotype for AV analysis was the clinical diagnosis established by the overloading phenylalanine test. Among the 51 PKU patients that we analyzed based on this trait, in 51% the predicted phenotype did not match the observed phenotype; the highest degree of concordance was found in patients with null/null genotypes. The genotype was observed to be a good predictor of the clinical course of the patients and significant correlations were found between phenylalanine values at first interview and predicted residual activity, genotype and arbitrary value sum.

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PKU in Minas Gerais State, Brazil: Mutation Analysis

Cited by 16 publications

References 34 publications

A preliminary mutation analysis of phenylketonuria in southwest Iran

A preliminary mutation analysis of phenylketonuria in southwest Iran

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

Variations in genotype-phenotype correlations in phenylketonuria patients

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