Phenylketonuria (PKU) is an inborn error of amino acid metabolism which is characterised by increased levels of phenylalanine as a result of a block in its conversion to tyrosine. This block is most commonly caused by an absence or deficiency of the enzyme phenylalanine hydroxylase (PAH).
PKU in its various forms occurs in approximately 1 in 10,000 births in Australia.
This block results in an increase in [phenylalanine] and a decrease in [tyrosine].
It is thought that the increase in [phenylalanine] is the cause of the severe mental retardation, since the early introduction of dietary phenylalanine restriction prevents or greatly reduces the phenotype from developing. The most severe functional block of the PAH enzyme is associated with the lowest tolerance for phenylalanine (so-called classical PKU), with less severe functional deficiencies of the PAH enzyme being associated with an ability to tolerate higher amounts of phenylalanine in the diet.
The mildest functional defects result in only a mild elevation of phenylalanine which does not require dietary phenylalanine restriction, and is sometimes known as benign hyperphenylalaninaemia.
The PAH gene is approximately 90 kb in length and lies on chromosome 12. It contains 13 exons. Infants inherit the defective enzyme in an autosomal recessive manner. As a result of the different mutations in the population, a high proportion of affected individuals are compound heterozygotes, i.e. they bear different mutations on each chromosome rather than homozygotes, who bear the same mutation on each chromosome. This explains much of the heterogeneity of the phenotype.
The mutations are generally single-base substitutions and microdeletions, many of which occur in the coding sequence resulting in a single amino acid change within the protein (missense mutation). Others occur at splice sites resulting in incorrect splicing of the primary RNA transcript (splice site mutation).
Large deletions of the gene (involving whole or multiple exons) are not common.
| Exon/ intron | Codon | Nucleotide change | Codon change | Severity in Homozygote | Pop. |
|---|---|---|---|---|---|
| E1 | 1 | ATG-GTG | Met-Val | Classic | French-Canadian |
| E3 | 3 | CGA-TGA | Arg-Ter | Classic | Asian |
| E5 | 158 | CGG-CAG | Arg-Gln | Classic | German, Swiss |
| E6 | 204 | TAT-TGT | Tyr-Cys | Mild PKU | Asian |
In recent years it has been recognized that some mutations in the PAH gene result in a mutant protein for which functional activity can be restored to some extent by giving pharmacological doses of the cofactor tetrahydrobiopterin (BH4), resulting in improved phenylalanine tolerance, with some individuals being able to come off a phenylalanine-restricted diet altogether.
General text on human molecular genetics:
Gelehrter TD, Collins FS and Ginsburg MD. Principles of Medical Genetics. Baltimore: Williams & Wilkins, 1998.
opac.library.usyd.edu.au/record=b2310731~S4
The above text should be read by any students who are not confident that they understand the way in which a gene is transcribed and then translated into protein.
General text on all aspects of molecular basis of PKU:
Scriver CR, Kaufman S. Hyperphenylalaninemia: Phenylalanine Hydroxylase Deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. (8th Ed.) New York: McGraw-Hill, 2001; 1667 - 1724.
opac.library.usyd.edu.au/record=b2436991~S4
E-Book 2002 at:
opac.library.usyd.edu.au/record=b2773371~S4
Blau N, Thny B, Cotton RGH, Hyland K. Disorders of Tetrahydrobiopterin and Related Biogenic Amines. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. (8th Ed.) New York: McGraw-Hill, 2001; 1725 - 1776.
opac.library.usyd.edu.au/record=b2436991~S4
E-Book 2002 at:
opac.library.usyd.edu.au/record=b2773371~S4 This text is excellent in that it gives all the details of the mutations (genotypes) and relates this to how the disease presents to the doctor (phenotype).
PAHdb - Phenylalanine Hydroxylase Knowledge base
This is an excellent and up to date online resource, which captures all known sequence variations in the PAH gene, has a wealth of information specific to PKU and its variants, and has links to a host of other useful sites.
BioPKU website
This website hosts databases of Pediatric Neurotransmitter Disorders (PND) including the database of PAH variations in PKU patients