Mutation analysis of thePAHgene in phenylketonuria patients from Rio de Janeiro, Southeast Brazil

Autor:	Isaura Ribeiro, Dulce Quelhas, Lúcia Lacerda, Nicole Mineiro, Francisco Ferraz Laranjeira, Márcia Gonçalves Ribeiro, Lilian de Mattos Carvalho, Alexandre L. Seabra, Eduardo Vieira Neto
Rok vydání:	2018
Předmět:	0301 basic medicine haplotypes Population phenylketonuria Biology Compound heterozygosity Frameshift mutation 03 medical and health sciences symbols.namesake Genotype Genetics Allele education Molecular Biology mutation analysis Genetics (clinical) Sanger sequencing education.field_of_study Haplotype Original Articles 030104 developmental biology PAH gene symbols Original Article epidemiology Brazil Founder effect
Zdroj:	Molecular Genetics & Genomic Medicine
ISSN:	2324-9269
DOI:	10.1002/mgg3.408
Popis:	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.
Databáze:	OpenAIRE
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