Characterization of Phenyalanine Hydroxylase Gene Mutations in Chilean PKU Patients

Hamilton, Valerie; María, Lorena Santa; Fuenzalida, Karen; Morales, Pamela; Desviat, Lourdes R.; Ugarte, Magdalena; Pérez, Belén; Cabello, Juan Francisco; Cornejo, Verónica

doi:10.1007/8904_2017_85

Cited by 10 publications

(21 citation statements)

References 23 publications

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“…These data were quoted from the present study in Rio de Janeiro, Hamilton et al. (), in Chile, and Vela‐Amieva et al. (), in Mexico…”

Section: Discussionsupporting

confidence: 82%

“…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%

“… Mutation previously described in Chile (Hamilton et al., ), Mexico (Vela‐Amieva et al., ), Spain (Aldamiz‐Echevarria et al., ; Trujillano et al., ) and/or Galicia (Couce et al., ) but haplotype not informed. …”

Section: Resultsmentioning

confidence: 99%

“…The splicing variant c.441+5G>T (IVS4+5G>T) was found in a patient whose other allele carried a large deletion of exon 5 (c.442‐?_509+?del). This pathogenic variant is frequent in Mexico and Chile, representing 7.3%, and 3.0% of the mutant alleles in PKU patients in those countries, respectively (Hamilton et al., ; Vela‐Amieva et al., ). The nonsense pathogenic variant c.618C>G (p.Y206*) was originally described on haplotype 1 (VNTR not determined) in a patient of Spanish ethnicity in Belgium (Michiels, Francois, Raus, & Vandevyver, ), see also the PAH db database (http://www.pahdb.mcgill.ca/?Topic=Search&Section=Main&Page=0).…”

Section: Discussionmentioning

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%

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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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“…These data were quoted from the present study in Rio de Janeiro, Hamilton et al. (), in Chile, and Vela‐Amieva et al. (), in Mexico…”

Section: Discussionsupporting

confidence: 82%

Section: Discussionmentioning

confidence: 84%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

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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Population and evolutionary genetics of the PAH locus to uncover overdominance and adaptive mechanisms in phenylketonuria: Results from a multiethnic study

et al. 2020

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Background: Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism in Europe. The reasons underlying the high prevalence of heterozygous carriers are not clearly understood. We aimed to look for pathogenic PAH variant enrichment according to geographical areas and patients' ethnicity using a multiethnic nationwide cohort of patients with PKU in France. We subsequently appraised the population differentiation, balancing selection and the molecular evolutionary history of the PAH locus. Methods: The French nationwide PKU study included patients who have been referred at the national level to the University Hospital of Nancy, and for whom a molecular diagnosis of phenylketonuria was made by Sanger sequencing. We performed enrichment analyses by comparing alternative allele frequencies using Fisher's exact test with Bonferroni adjustment. We estimated the amount of genetic differentiation among

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Expanding diversity within phenylketonuria in ecuadorian patients: genetic analysis and literature review of newborn screenings

Aguirre,

Haro,

Campodónico

et al. 2024

BMC Pediatr

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Characterization of Phenyalanine Hydroxylase Gene Mutations in Chilean PKU Patients

Cited by 10 publications

References 23 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

Population and evolutionary genetics of the PAH locus to uncover overdominance and adaptive mechanisms in phenylketonuria: Results from a multiethnic study

Expanding diversity within phenylketonuria in ecuadorian patients: genetic analysis and literature review of newborn screenings

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