The PQBP1 (Polyglutamine tract-binding protein 1) gene encodes a nuclear protein that contains a WW domain and regulates pre-mRNA splicing.  Mutations in the PQBP1 gene were reported in several X chromosome-linked mental retardation (XLMR) disorders including Golabi-Ito-Hall (GIH) syndrome.  The mutation that causes GIH syndrome maps within the WW domain of PQBP1 and substitutes Tyrosine 65 (Y65) with Cysteine (C).  We showed that the binding property of the Y65C mutated WW domain and the full-length mutant protein toward its cognate proline-rich ligands was diminished. In GIH patient-derived lymphoblasts, the complex between PQBP1-Y65C and WBP11 (WW domain binding protein 11) splicing factor was compromised. In these cells, a substantial decrease in pre-mRNA splicing efficiency was detected. Our study points to the critical role of the WW domain in the function of the PQBP1 protein and provides insight into the molecular mechanism that underlies GIH syndrome.  Our current work is focused on the generation of animal models of GIH in order to study the mRNA splicing defect in the brain.

Figure 1. Hippo Signaling Pathway is Rich in WW Domain Complexes.  Orange color components of the pathway represent proteins either with WW domain or its cognate, PPxY motif-containing ligand. For more details see: Sudol, M., and Harvey, K. (2010) TiBS, 35, 627-633.

Figure 2. Y65C WW Mutation in PQBP1 Targets a Hydrophobic Core of the Domain and Affects mRNA Splicing.  Tapia, V.E. et al., (2010) J. Biol. Chem. 285, 19391-19401.

Figure 3.  Pictures from the Sudol Laboratory from 2009 and 2010.