Phenylalanine hydroxylase is an enzyme that catalyzes the rate limiting step in the catabolism of phenylalanine, thereby facilitating its clearance. Specifically, this enzyme catalyzes the conversion of L-phenylalanine to L-tyrosine. Phenylalanine is taken into the body by way of food, but instead of being used for protein synthesis, most of this amino acid is converted to tyrosine and undergoes further metabolism to form neurotransmitters and hormones. This conversion is very important, as shown by individuals in whom this mechanism is defective. Mutations in the PAH gene give rise to Phenylketonuria (PKU), a condition in which pheylalanine accumulates to toxic levels in the blood and brain, resulting in severe consequences, including mental retardation.
The PAH gene is located on the long arm of chromosome 12. The gene contains 13 exons, and has a length of close to 80 Kb. The enzyme itself, which belongs to the biopetrin-dependent aromatic amino acid hydroxylase family, is composed of 452 amino acids, and has a size of more than 50 kDa. The protein is actually a tetramer, and each of the four subunits is made up of three distinct domains. These are a 33 kDa catalytic domain, a 12-19 kDa N-terminal regulation domain, and a 5 kDa C-terminal tetramerization domain. The tetramerization domain is made up of two beta strands forming a ribbon, and a long helix. These four helices form a coiled-coil that keeps the quaternary structure of the protein together. The gene is expressed in both the liver and the kidney.
More than 500 mutations have been identified in the PAH gene. These include missense mutations, as well as deletions. The most common of these is a missense, R408W mutation. Mutations that cause an almost complete reduction of the enzyme activity result in the classic or severe form of PKU, whereas other mutations that leave residual enzyme activity lead to milder versions of the condition, such as non-PKU hyperphenylalaninemia.
[See: Kuwait > Bender et al., 1994].
Bender et al. (1994) studied the PAH gene in four Kuwaiti and four Egyptian families with at least one child affected with PKU and 13 unaffected Kuwaiti controls. A quarter of the PKU chromosomes showed haplotype 7, while haplotypes 1, 4, 5, and 6, were detected on 67% of the PKU chromosomes. This was in contrast to the normal chromosomes, where haplotypes 1, 2, 4, and 7 were found in 50% of the cases, while the rest were found on rare haplotypes, including haplotypes 11, 32, 36, and 3 other unclassified haplotypes. Interestingly, digestion with MspI revealed a polymorphism in one Egyptian family as well as one of the controls. This polymorphism had previously been described among Black Americans, although on a different haplotype. Bender et al. (1994) speculated that this mutation might have originated in Africa, and then spread to Arabia.