Difference between revisions of "Phenylketonuria 2011"

From Bioinformatikpedia
(Reference sequence)
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=== Reference sequence ===
=== Reference sequence ===
* [[phenylalanine_hydroxylase_reference|reference]]
* [[phenylalanine_hydroxylase_reference| amino acid sequence]]
=== Neutral mutations ===
=== Neutral mutations ===

Revision as of 16:02, 11 May 2011

still under construction


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 is 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

Neutral mutations

Disease causing mutations

There are 509 disease causing mutations known (HGMD).