The most prevalent allele identified in persons
of European descent with the
metabolic disease Phentylketonuria (PKU) is a single base change (GT-to-AT in the sense
strand) that corresponds to a change in the 5'-GU splice donor site
of Intron 12
to 5'-AU. This
makes the site unrecognizable by the splicing enzymes. During
intron excision, the A
site in Intron 12 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 the last 52 amino
acids at the C-terminus.
This results in an unstable protein with almost zero PAH activity.