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Molecular genetics of phenylketonuria in Mediterranean countries: a mutation associated with partial phenylalanine
1Clinique et Unité de Recherches de Génétique Médicale, INSERM U-12, Hôpital des Enfants Malades, Paris.
Abstract:
We report the characterization of a mutation in the phenylalanine hydroxylase (PAH) gene associated with partial residual activity of the enzyme. This point mutation (280glu----lys) was found by sequencing a mutant cDNA clone derived from a needle biopsy of the liver in a child with variant form of phenylketonuria. There is a strict concordance between homozygosity for the mutation and this particular phenotype. The (280glu----lys) mutation is linked to an original and rare RFLP haplotype at the PAH locus found in south Europe and North Africa. So far, this genotype-haplotype association is both inclusive and exclusive. Thirty-three PAH-deficient patients were screened for the mutation by using polymerase chain-reaction amplification of their genomic DNA extracted from Guthrie cards. Since a large number of patients can be screened for a particular mutation by using Guthrie cards, the possibility arises of using these samples collected by national newborn screening centers for prospective and retrospective detection of other mutations in the human genome.
Insights
A specific mutation in the phenylalanine hydroxylase (PAH) gene, (280glu----lys), is linked to a variant form of phenylketonuria (PKU). This finding aids in diagnosing and understanding PKU, with potential for broader genetic screening.
Area of Science:
- Genetics
- Biochemistry
- Medical Science
Background:
- Phenylketonuria (PKU) is a genetic disorder.
- It results from mutations in the phenylalanine hydroxylase (PAH) gene.
- Understanding specific mutations aids in diagnosis and treatment.
Purpose of the Study:
- To characterize a novel mutation in the PAH gene.
- To investigate its association with a variant form of PKU.
- To explore its utility in genetic screening.
Main Methods:
- Sequencing of a mutant cDNA clone from a liver biopsy.
- Polymerase chain-reaction (PCR) amplification of genomic DNA from Guthrie cards.
- Restriction fragment length polymorphism (RFLP) haplotype analysis.
Main Results:
- A specific point mutation (280glu----lys) in the PAH gene was identified.
- This mutation is strictly associated with a variant PKU phenotype.
- The mutation is linked to a rare RFLP haplotype prevalent in South Europe and North Africa.
Conclusions:
- The (280glu----lys) mutation is a key genetic marker for a specific PKU phenotype.
- The genotype-haplotype association is highly specific.
- Guthrie cards offer a viable method for large-scale mutation screening in PKU and other genetic disorders.