Splice-Site mutations in the PAH gene

     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.

Text material © 2011 by Steven M. Carr