The most prevalent allele identified in persons
of European descent with the
metabolic disease Phenylketonuria (PKU) is a single base mutation (GT-to-AT in the DNA
sense strand) that corresponds to a change from 5'-GU to 5'-AU in the
splice donor site of Intron 12.
This makes the site unrecognizable by the splicing enzymes. During
intron excision, the A
site in Intron 12 bypasses the
altered site, attaches incorrectly to the 5'-GU site of Intron 11, and excises Exon
12 along with Introns
11 & 12.
Analysis of cDNA clones
confirms that individuals with this mutation have a 156bp
deletion in the mRNA,
corresponding precisely to the length of Exon 12.
This leads to a truncated PAH protein
that lacks 52 amino acids
at the C-terminus. This
result is an unstable protein with almost zero PAH activity.