Presenter: Willem Griffiths
Faculty Mentor: Jennifer Phillips, Judy Pierce
Presentation Type: Poster 65
Primary Research Area: Science
Major: Biology
Usher syndrome (USH) is the most frequent cause of hereditary deaf-blindness, accounting for over 50% of the deaf- blind population. USH type 1F, one of the most severe forms of USH, is rare globally, but the Founder effect has made it the most prevalent type of USH in the Ashkenazi Jewish population. USH1F patients have profound congenital deafness and early-onset progressive vision loss due to photoreceptor degeneration. USH1F is caused by mutations in the PCDH15 gene, which encodes a large, multidomain cell adhesion protein. The truncated PCDH15 protein disrupts the organization of stereocilia in the inner ear and leads to dysfunction and eventual death in photoreceptor cells. Due to the size and complex alternative splicing of PCDH15, the straightforward gene-replacement therapies being pursued for other forms of USH are not feasible for this gene. We are testing the feasibility of using an antisense splice-inhibitor to delete Exon 8 from the PCDH15 transcript. Although the resulting protein would be slightly shorter than normal, all downstream functional domains would remain intact, so it is possible that this modified form of PCDH15 would maintain its functional integrity in the absence of Exon 8. Zebrafish mutants with nonsense mutations in the orthologous pcdh15 exon have been generated via targeted mutagenesis using CRISPR/Cas9 gene editing. These loss of function mutants display phenotypes characteristic of human USH1F. The Exon 8 splice-blocking oligonucleotides will be tested on these mutants in order to determine whether the modified pcdh15 protein can rescue the phenotype.