3-29

Allelic Variation for Phenylalanine Hydroxylase & Phenylketonuria


    The Phenylalanine Hydroxylase (PAH) locus includes 14 introns [black bars] widely separated by 13 exons [green bars]. The 2007 OMIM list included 67 allelic variants known to affect enzymatic activity at this locus. The locations of the mutations involved are shown above. All exons and most introns have at least one known mutation. The table below shows that about one-third produce non-clinical elevation of blood phenylalanine levels (hyperphenylalanemia). Among the remaining two-thirds that lead to PKU, more than half are mis-sense mutations leading to amino acid substitutions. The rest are more or less equally divided among nonsense mutations ('Stops'), deletions, and post-transcriptional splicing errors in introns (intervening sequence or IVS mutations). [in 2013, the OMIM list includes nearly 600 allelic variants].

    Note, however, that this list is based on PAH variants that have come to the attention of physicians or investigators. The (large?) majority of mutations at this locus probably have no effect on the phenotype, and hence have gone undetected.


Mutation
#
%
Non-PKU hyperphenylalanemia
19
-
Phenylketonuria (PKU)
47
100
Splice-site mutations
7
14
Deletion mutations, including:

12
     Complete exon
1

     Single triplet
2

     Five triplets
1

     Frame shift premature termination
2

Non-sense mutations
9
18
Miss-sense mutations
27
55


All text material 2013 by Steven M. Carr