IVS12DS, G-A, +1
The commonest mutation is found at the exon 12 donor splice site, reffered to as IVS12DS, G-A, +1. This will cause skipping of the 12th exon when the RNA is being spliced. This essentially means that the mRNA produced will contain a stop codon too early within the reading frame and so the protein produced at translation will be truncated and inactive. This occurs because of a single base substitution, GT to AT. The protein will in fact be 52 amino acids shorter than normal (Marvit et al, 1987). Patients with this mutation will suffer from classic PKU.

Arg408 to Trp
This mutation is by a transition from CGG to TGG in exon 12. This will result in an amino acid substitution of Arg to Trp at position 408in the PAH gene (DiLella et al 1987). This is small mutation and is sufficient enough to cause PKU even though only one amino acid is different.

Arg261 to Gln
The substitution in exon 5 Arg261 to Gln does not result in completely inactive PAH (Superti-Furga et al, 1991). The condition it causes is called Benign Hyperphenylalaninemia. More than 5% of the enzyme is fully functional and so raised blood phenylalanine is only about 10% greater than in non-affected individuals. The treatment for PKU in these individuals need not be so closely adhered to. However, phenyalanine levels can become high enough during pregnancy to damage the foetus so treatment before conception and during pregnancy must be undertaken more strictly.

Arg158 to Gln
The mutation is a substitution from G to A within the Arg 158 position causing the amino acid to be replaced by Gln. This is only sufficient to cause a mild form of the disease. As mentioned above, they have a slightly higher residual enzyme activity and less need to comply strictly to a low phenylalanine diet.

MODE OF INHERITANCE
Phenylketonuria is an autosomal recessive disorder present from birth. This means that a affected individual must have gained a mutant allele from both parents. This can have occured in three possible ways.

Click here to see a diagram showing the inheritance of PKU from two parental carriers.

When considering a whole family pedigree it is often siblings who have the disease. This can be reffered to as Horizontal Transmission. Other relatives can be affected but this usually only occurs in large inbred families. However, when two carriers meet there is still only a 25% chance of them giving any one child PKU. The disease affects women and men equally but there are, perhaps, greater implications for a woman suffering from PKU as she has to take the disease into account before she has children (see treatment section).

A recessive trait is more commonly expressed if parents are related. This is because 2 carriers of the same recesive gene are more likely to unite. This is termed consanguinity and it usually takes place between cousins. This is more likely to be relevant if the condition is rare. The frequency of PKU is 1 in 10,000 live births which for an autosomal recessive condition is relatively common and so consanguinity may not play a big role in PKU.

It is important when considering pregnancies of PKU sufferers or carriers to consider the possiblity that their child will be a PKU sufferer or carrier.
Pregnancies between a sufferer and a non-carrier will yield all offspring as carriers. To see an illustration of this click here.
There is in the general population a carrier frequency of 1 in 50 and this means that the likelihood of a sufferer meeting a carrier by chance and then having a PKU suffering child is 1 in 100. This is illustrated here.

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