Dataset Information

Analysis of EX5del4232ins268 and EX5del955 PAH gene mutations in Ukrainian patients with phenylketonuria.

ABSTRACT: Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by deficiency of phenylalanine hydroxylase (PAH). The major molecular defects causing PKU are missense mutations of PAH gene. Large deletions of exon 5 (EX5del955 and EX5del4232ins) were first reported by the Czech study and were later found also in the Polish, Slovak, Slovenian and Italian PKU-patients. These observations demonstrate the existence of a common subset of this mutation predominantly among Central European populations of Slavic descent. That is why we suggest that EX5del1955 and EX5del4232ins268 mutations might be frequent causes of PKU in Ukrainian patients. EX5del955 and EX5del4232ins268 mutations were analyzed in 106 unrelated PKU patients negative for PAH gene mutations on one or both alleles from our previous analysis. The simultaneous detection of EX5del4232ins268 and EX5del955 mutations was performed by PCR amplification of mutant alleles. EX5del955 mutation was not detected in the Ukrainian patients. This relative alleles frequency of EX5del4232ins268 mutation in the Ukrainian PKU population was determined as 1,66%. Our findings can be the one more evidence of Central European Slavic origin of EX5del4232ins268 mutation, suggested previously. This finding is important for the improvement of DNA diagnosis necessary for the management of PKU patients from Ukraine.

SUBMITTER: Pampukha V

PROVIDER: S-EPMC6136599 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Analysis of EX5del4232ins268 and EX5del955 <i>PAH</i> gene mutations in Ukrainian patients with phenylketonuria.

Pampukha Volodymyr V Nechyporenko Maryna M Livshyts Ludmila L

Genes & diseases 20161214 2

Phenylketonuria (PKU) is an autosomal recessive metabolic disorder caused by deficiency of phenylalanine hydroxylase (PAH). The major molecular defects causing PKU are missense mutations of <i>PAH</i> gene. Large deletions of exon 5 (EX5del955 and EX5del4232ins) were first reported by the Czech study and were later found also in the Polish, Slovak, Slovenian and Italian PKU-patients. These observations demonstrate the existence of a common subset of this mutation predominantly among Central Euro ...[more]

PMID: 30258912

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Project description:BACKGROUND:Phenylketonuria (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. METHODS:A 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. RESULTS:Nine (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]. CONCLUSION:The 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.

Dataset Information

Analysis of EX5del4232ins268 and EX5del955 PAH gene mutations in Ukrainian patients with phenylketonuria.

Publications

Analysis of EX5del4232ins268 and EX5del955 <i>PAH</i> gene mutations in Ukrainian patients with phenylketonuria.

Similar Datasets

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