The PAH gene mutation

The PAH gene is found on chromosome 12. It has 13 exons and encodes for 452 amino acids. PKU can be resulted by either mutations at the PAH locus or mutations in a number of loci which effect BH₄ synthesis and regeneration.

The mutation is pathogenic as it disrupt the structure and function of the enzyme. There are about 500 disease-causing mutations identified in patients with PKU. The human PAH gene shows great allelic variation . Pathogenic mutation can happens in all PAH gene exons. 

The percentage of different types of mutation that can occur in the gene are as followed:

The classic PKU is resulted by the mutation within the PAH gene, leading to amino acid substitution or premature stop sodon. A number of alleles combination at PAH locus are detected. 3/4 of the European patients have different mutation in their 2 copies of PAH gene. Point mutation in exon 3 of PAH gene from arginine 111 to tryosine 111 is the main cause for mutations in PAH gene. A point mutation by changing a G to A in exons 7 changes glutamate to lysine at protein 280. Replacing nucleotide C to T in exon 9 changes leucine to proline which is the 311th amino acid in the protein sequence. When a thymine replaces cytosine in exon 12, tyrosine 408 is formed instead of arginine 408.

This causes the protein sequence formed to be different and the enzyme will fold differently and become non-functional. As a result, L-Phe cannot be digest by PAH. L-Phe then go through other metabolic pathway and form many toxic metabolites which will accumulate in the body and cause mental retardation.
References:

1. Genetics of Phenylketonuria. Retrived July 1, 2012, from http://www.uic.edu/classes/phar/phar332/Clinical_Cases/aa%20metab%20cases/PKU%20Cases/genetics1.htm

2. Robin A Williams,Cyril DS Mamotte, John R Burnett. (2008). Phenylketonuria: An Inborn Error of Phenylalanine Metabolism. National Center for Biotechnology Information. Retrieved July 2, 2012, from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2423317/

3. Nariman Hossein-Javaheri. (2012). Phenylketonuria. Tangient LLC. Retrieved July 10, 2012, from https://neurowiki2012.wikispaces.com/Phenylketonuria