Molecular biology of phenylketonuria

Güttler, Flemming; DiLella, Anthony G.; Ledley, Fred D.; Lidsky, Alan S.; Kvok, S. C. M.; Marvit, J.; Woo, Savio L. C.

doi:10.1007/bf00442048

Cited by 16 publications

(2 citation statements)

References 15 publications

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“…Whereas the combined frequency of haplotypes 2 and 3 comprise 58% of all mutant alleles in the Danish, and 37% in the German population, in Poland haplotype 2 was most prevalent. In our study 56.8% of the mutant alleles were associated with HT2, whereas only 2.3% were found in association with HT 3, which accounts for a large proportion of the PKU alleles in Denmark (38% ; Giittler et al 1987) and gradually declines in frequency towards south-eastern Europe, e.g., 13% in Western Germany, 2.3% in Poland and virtually absent in Bulgaria. These differences, and the finding of five previously unreported haplotypes in the Polish population, support the hypothesis that PKU is a highly heterogeneous disease and has resulted from several mutations which have developed independently in different populations.…”

Section: Discussioncontrasting

confidence: 64%

Molecular analysis of PKU haplotypes in the population of southern Poland

Zygulska¹,

Eigel

Aulehla-Scholz

et al. 1991

Hum Genet

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Out of a population of 138,598 infants born in southern Poland between 1987 and 1989, and screened for phenylketonuria (PKU), 28 cases were ascertained probands and their parents were isolated and eight polymorphic restriction sites were analyzed within the phenylalanine hydroxylase gene region. Twenty-one different haplotypes (HT) were revealed, five of them representing new categories. The most common haplotypes among those carrying normal alleles were: HT1 (27.3%) and HT4 (11.4%). Within the group of haplotypes with mutant alleles the most frequent was HT2 (56.8%), whereas the frequency of this haplotype in other European populations, such as French, Danish and German, ranged from 12% to 24%. HT3, being the most common in Danish (38%), and relatively frequent in the other western European (13-14%) populations, appeared to be very rare in our sample (2.3%). The mutation of codon 408 (exon 12, C----T, Arg----Trp), which has been described to be tightly linked to HT2, was tested on amplified DNA by dot-blot hybridization. This mutation was found in 25 out of 44 proband chromosomes. In one case it was linked to HT5, in the remaining 24 to HT2. Our results confirm molecular heterogeneity of PKU haplotypes, as well as their significant interpopulation variation.

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Section: Discussioncontrasting

confidence: 64%

Molecular analysis of PKU haplotypes in the population of southern Poland

Zygulska¹,

Eigel

Aulehla-Scholz

et al. 1991

Hum Genet

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“…A correlation between $7 RFLP haplotypes and metabolic phenotypes were observed [ 16] and this information formed a strategy for sequencing the first two PKU alleles in children with classical PKU [15]. Later, expression of PAH mutations was measured and it was demonstrated that each PAH mutation has a particular quantitative effect on enzyme activity [23].…”

Section: Introductionmentioning

confidence: 97%

The influence of mutations on enzyme activity and phenylalanine tolerance in phenylalanine hydroxylase deficiency

Güttler

Guldberg

1996

Eur J Pediatr

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The phenylalanine hydroxylase (PAH) deficiency trait is heterogeneous with a continuum of metabolic phenotypes ranging from classical phenylketonuria (PKU) to mild hyperphenylalaninaemia (MHP). More than 200 mutations in the PAH gene are associated with PAH deficiency. From theoretical considerations or in vitro expression studies each mutation has a particular influence on enzyme activity, which explains the variation in dietary tolerance for phenylalanine (Phe). This paper gives a summary of the effect of each type of mutation on PAH activity and illustrates how the combination of mutations (the genotype) is associated with the Phe tolerance (the metabolic phenotype). Mutations within a population generally include a few prevalent mutations and a high number of rare mutations. The particular distribution of mutations implies that many PAH-deficient patients carry the same mutation combination, enabling the establishment of genotype-phenotype correlations by comparing clinical parameters in patients with identical genotypes. Because certain mutations always cause MHP irrespective of the mutation on the second allele, mutation typing of hyperphenylalaninaemic neonates will differentiate between PKU and MHP. In addition, genotyping will provide a tool for precise diagnosis of the metabolic phenotype of the neonate with PKU and thereby permit earlier implementation of dietary therapy better tailored to each individual patient.

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