Splice-Site mutations in the PAH gene
[NCBI dbSNP - Short Genetic Variations database]

     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.

Text material © 2014 by Steven M. Carr