Phenylketonuria 2011

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Revision as of 18:05, 11 May 2011 by Pfeiffenberger (talk | contribs) (The PAH gene)

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Phenylketonuria causes several syndromes:

  • Delayed mental and social skills
  • Head size significantly below normal
  • Hyperactivity
  • Jerking movements of the arms or legs
  • Mental retardation
  • Seizures
  • Skin rashes
  • Tremors
  • Unusual positioning of hands


The enzyme phenylalanine hydroxylase catalyzes the conversion of phenylalanie to tyrosine. If the function of phenylalanine hydroxlase is reduced by at least ... % the organism has phenylketonuria. The amount of phenylalanine in the blood rises to harming concentrations, which leads to several symptoms (see above). The more aggrevate symptoms are due to disturbances in the brain development.


See also description of this disease in

Biochemical disease mechanism

Phenylalanine hydroxylase is involved in the phenylalanine pathway. It catalyses the conversion of phenylalanine to tyrosine. It's the major way to reduce the concentration of phenylalanine. In phenylketonuria the function of this protein is reduced by at least ... %. The missing reduction of phenylalaine leads to harmful concentrations of phenylalanine. The enzyme ... is responsible for the transport of large neutral amino acids across the blood brain barrier. Through the high concentration of phenylalanine other large neutral amino acids are less frequently transported to the brain. These missing amino acids cause severe problems in the brain development.


The PAH gene

The PAH gene, also known as phenylalanine hydroxylase, is located on the long arm of the autosomal chromosome 12 between positions 22 and 24.2 in humans. The precise location is defined from base pairs 103,232,103 to 103,311,380 which results in a total length of 79,277 bps on the chromosome. This gene consists of 13 exons and 12 introns, after the exons of the pre-mature mRNA are spliced away a length of only 2,681 bps is left on the transcript. This means only 3.38% of the original gene size are left on the mature mRNA. However, the full length of a functional phenylalanine hydroxylase protein is in the end 452 residues long.

Individuals who suffer from Phenlyketonuria require two mutated alleles of the PAH gene of which the protein product has to be severe dysfunctional in its ability to catalyze the transformation from phenylalanine to tyrosine. This is only possible when both healthy parents carry one dysfunctional allele on their chromosome 12. Their offspring's will then have a 25% chance to be affected from phenylketonuria because these individuals inherited both dysfunctional PAH alleles from their parents. Furthermore, there is only a 25% for their offspring's to be a non-carrier of a dysfunctional allele and obviously a 50% to inherit exactly one dysfunctional allele of the PAH gene.

Protein function

A properly functional phenylalanine hydroxylase protein realizes the transformation from phenylalanine to tyrosine by hydroxylating the substrate, in our case phenylalanine. More precisely, it adds a OH group to the 4th position of the 6-carbon aromatic ring of phenylalanine, thus resulting in a tyrosine.

However, phenylalanine hydroxylase requires three helper molecules for the process which are <math>O^2</math>



The PAH gene is located on a highly heterogenic locus, by now there are 642 mutations for the PAH gene known {TODO add HGMD reference}. 509 of these mutations could be associated with the disease phenylketonuria {TODO add HGMD reference}.

Mutation types

The 3 most common mutation types for the PAH gene locus are missense, deletion and splice junction mutations with 60%, 13.48% and 10.99% respectively.


Gene region of mutations

After analyzing the gene regions of known mutations we found out that most mutations are located on exons of the PAH gene. The exons E7, E6, E11 and E3 contain 15.43%, 13.83%, 8.87%, 8.69% and 7.80% respectively of all mutations. In contrast, almost all introns of PAH (with only a few exceptions) contain less than 1% of all known mutations. However this seems to be somehow not surprising since more than 60% of all mutations are of type missense.


Position of the mutations on the phenylalanine hydroxylase protein

70% of all disease associated mutations are located on the catalytic domain of phenylalanine hydroxylase. Whereas the regulatory domain and the tetramerisation domain contain 16% and 14% respectively of all disease associated mutations.


  • Nenad Blau, Francjan J van Spronsen, Harvey L Levy . Phenylketonuria. Lancet 2010; 376: 1417–27

Mutations by ethnicity

The occurrence of mutations for the PAH locus on chromosome 12 is unevenly distributed among populations. For example most mutations could be found among people with English or German ethnicity with 5.98% and 5.79% respectively. The distribution for the first eight ethnic groups is as follows:

  • English: 5.98%
  • German: 5.79%
  • Spanish: 5.14%
  • American: 4.48%
  • French-Canadian: 4.20%
  • Italian: 4.14%
  • Norwegian: 3.74%
  • Belgian: 3.71%


Reference sequence

The following links contain the reference sequence of the PAH gene

Neutral mutations

Disease causing mutations

There are 509 disease causing mutations known (HGMD).