A missense mutation, S349P, completely inactivates phenylalanine hydroxylase in North African Jews with phenylketonuria

Michal Weinstein*, Randy C. Eisensmith, Véronique Abadie, Smadar Avigad, Stanislas Lyonnet, Gerard Schwartz, Arnold Munnich, Savio L.C. Woo, Yosef Shiloh

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

The majority of hyperphenylalaninemias (HPAs) result from mutations at the gene for phenylalanine hydroxylase (PAH). The broad phenotypic variability of these conditions, ranging from phenylketonuria (PKU) to mild benign HPA, is underlain by a wide spectrum of mutations giving rise to various genotypic combinations. Mutant PAH alleles, labeled by specific polymorphic haplotypes and mutations, are becoming useful markers in human population genetics. We report here a mutant PAH allele found in Jews from Morocco and Tunisia, marked by haplotype 4 and a missense mutation, TCASer→CCApro, at codon 349 in exon 10 of the gene. In vitro expression of the mutation showed normal levels of mRNA with virtually no enzymatic activity or protein immunoreactivity, pointing to a highly unstable protein. A homozygote for this mutation showed the most severe ("classical") type of PKU, while compound heterozygotes showed two other types of HPA - "atypical" PKU and "high benign" HPA - illustrating the interplay between different mutations that gives rise to various HPAs.

Original languageEnglish
Pages (from-to)645-649
Number of pages5
JournalHuman Genetics
Volume90
Issue number6
DOIs
StatePublished - Feb 1993

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