Splicing of phenylalanine hydroxylase (PAH) exon 11 is vulnerable: Molecular pathology of mutations in PAH exon 11

Heintz C., Dobrowolski S. F., Andersen H. S., Demirkol M., Blau N., Andresen B. S.

MOLECULAR GENETICS AND METABOLISM, vol.106, no.4, pp.403-411, 2012 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 106 Issue: 4
  • Publication Date: 2012
  • Doi Number: 10.1016/j.ymgme.2012.05.013
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.403-411
  • Istanbul University Affiliated: Yes


In about 20-30% of phenylketonuria (PKU) patients, phenylalanine (Phe) levels can be controlled by cofactor 6R-tetrahydrobiopterin (BH4) administration. The phenylalanine hydroxylase (PAH) genotype has a predictive value concerning BH4-response and therefore a correct assessment of the mutation molecular pathology is important. Mutations that disturb the splicing of exons (e.g. interplay between splice site strength and regulatory sequences like exon splicing enhancers (ESEs)/exon splicing silencers (ESSs)) may cause different severity of PKU. In this study, we identified PAH exon 11 as a vulnerable exon and used patient derived lymphoblast cell lines and PAH minigenes to study the molecular defect that impacted pre-mRNA processing. We showed that the c.11441>C and c.1066-3C>T mutations cause exon 11 skipping, while the c.1139C>T mutation is neutral or slightly beneficial. The c.1144T>C mutation resides in a putative splicing enhancer motif and binding by splicing factors SF2/ASF, SRp20 and SRp40 is disturbed. Additional mutations in potential splicing factor binding sites contributed to elucidate the pathogenesis of mutations in PAH exon 11.