Open AccessMutation analysis of the PAH gene in phenylketonuria patients from Rio de Janeiro, Southeast Brazil
Author(s) -
Vieira Neto Eduardo,
Laranjeira Francisco,
Quelhas Dulce,
Ribeiro Isaura,
Seabra Alexandre,
Mineiro Nicole,
d. M. Carvalho Lilian,
Lacerda Lúcia,
G. Ribeiro Márcia
Publication year - 2018
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.408
Subject(s) - genetics , frameshift mutation , missense mutation , sanger sequencing , compound heterozygosity , genotype , gene , haplotype , biology , allele , population , multiplex ligation dependent probe amplification , genomic dna , mutation , microbiology and biotechnology , medicine , exon , environmental health
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%), IVS 10‐11G>A (10.3%), IVS 2+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, IVS 10‐11G>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 IVS 2+5G>C, p.G352Vfs*48, and IVS 12+1G>A were also detected. Genetic drift and founder effect may have also played a role in the mutation spectrum we observed.