Oculopharyngeal muscular dystrophy (OPMD) is an adult onset disease characterized by eyelid drooping and difficulties in swallowing, with weakness also noted in proximal limb muscles. No cure exists for this disease. The mutation responsible for the disease is found within the polyadenylate-binding protein nuclear 1 (PABPN1) gene. The ubiquitously expressed PABPN1 protein regulates post-transcriptional gene expression through modulating 3'-end formation including poly(A) tail length and 3'-end cleavage/polyadenylation site selection. The autosomal dominant form of OPMD, which is the most common form of the disease, is characterized by a polyalanine expansion in the N-terminal domain of the protein from the normal 10 alanines to 12-17. Patients with autosomal dominant OPMD have one mutant allele of PABPN1 and one normal allele of PABPN1. However, current mouse models of OPMD are transgenic and thus contain two normal alleles of PABPN1 in addition to one mutant allele of PABPN1 leading to significant overexpression of PABPN1. Thus, these mouse models do not accurately reflect the genotype of patients afflicted with the disease. We have created a knock- in mouse model that expresses PABPN1 containing a polyalanine expansion of 17 alanines (Ala17PABPN1) in the presence of Cre-recombinase and is thus more closely aligned with the genetic changes in autosomal dominant OPMD patients. The goal of this proposal is to thoroughly understand the effects of Ala17PABPN1 on muscle pathology and function (Aim 1) as well as to begin to examine the impact on post-transcriptional processing of RNA (Aim 2) throughout the lifespan of these Ala17PABPN1 knock-in mice. We propose that this new mouse model will be invaluable for future studies in understanding the tissue-specific consequences of mutant PABPN1 and testing potential therapies.
We will characterize genetically engineered mice with the same change in their genes as people who suffer from Oculopharyngeal Muscular Dystrophy. These mice will be the first opportunity to accurately model this disease in mice and could provide tools both for understanding how the disease affects specific muscles and, importantly, for finding therapies to treat the disease and improve the quality of life for people afflicted wit this disease.