Oculopharyngeal muscular dystrophy (OPMD) is a rare autosomal dominant disease of late onset for which no cure exists. It is characterized primarily by eyelid drooping and difficulties in swallowing with some weakness in proximal limb muscles. Although mutations in the ubiquitously expressed PABPN1, an mRNA binding protein, cause OPMD, much is still unknown regarding the mechanism by which mutant PABPN1 leads to muscle-specific pathology. In autosomal dominant OPMD one mutant allele of PABPN1 replaces one normal allele of PABPN1. Thus, pathology could be due to the loss of one normal allele, the gain of a mutant allele or the combination of both events. Due to the fact that PABPN1 appears to play an essential role in RNA metabolism, any impairment of its function should, in theory, affect numerous cell and tissue types, but the intrinsic characteristics of skeletal muscle may make this tissue more vulnerable to the effects of mutant PABPN1. Indeed, our preliminary data reveal that muscle tissue shows significantly lower levels of PABPN1 protein as compared to unaffected tissues. We hypothesize that the lower amount of PABPN1 in skeletal muscle could sensitize this tissue to the deleterious effects of mutant PABPN1. The overall goal of this proposal is to examine how both mutant PABPN1 and decreased functional levels of wild type PABPN1 impact RNA biogenesis and myogenesis. Thus, we will analyze the consequences of expressing mutant PABPN1 in muscle cells (Aims 1 and 2). We will exploit a PABPN1 knockout mouse to determine whether a decrease in PABPN1 is sufficient to cause muscle pathology or sensitize cells to the expression of mutant PABPN1 (Aim 2). Finally, we will identify RNAs that are altered in response to decreased functional levels of PABPN1 in muscle cells and consider key muscle functions for these putative PABPN1 targets (Aim 3). Importantly, the Specific Aims are designed to understand the muscle-specific role of PABPN1, which is critical for understanding the pathogenesis of OPMD. The knowledge gained from our studies is likely to afford new therapeutic strategies that target the appropriate molecular pathways altered in the muscles of OPMD patients.

Public Health Relevance

We are studying why mutations in the mRNA binding protein PABPN1 lead to oculopharyngeal muscular dystrophy. We seek to understand why ubiquitous expression of mutant PABPN1 leads to disease only in muscle. This knowledge will allow development of therapies for this disease to target the appropriate molecular pathways impacted in patients.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MOSS-A (02))
Program Officer
Nuckolls, Glen H
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
Schools of Medicine
United States
Zip Code
Vest, Katherine E; Phillips, Brittany L; Banerjee, Ayan et al. (2017) Novel mouse models of oculopharyngeal muscular dystrophy (OPMD) reveal early onset mitochondrial defects and suggest loss of PABPN1 may contribute to pathology. Hum Mol Genet 26:3235-3252
Banerjee, Ayan; Vest, Katherine E; Pavlath, Grace K et al. (2017) Nuclear poly(A) binding protein 1 (PABPN1) and Matrin3 interact in muscle cells and regulate RNA processing. Nucleic Acids Res 45:10706-10725
Vest, Katherine E; Apponi, Luciano H; Banerjee, Ayan et al. (2015) An Antibody to Detect Alanine-Expanded PABPN1: A New Tool to Study Oculopharyngeal Muscular Dystrophy. J Neuromuscul Dis 2:439-446
Randolph, Matthew E; Phillips, Brittany L; Choo, Hyo-Jung et al. (2015) Pharyngeal Satellite Cells Undergo Myogenesis Under Basal Conditions and Are Required for Pharyngeal Muscle Maintenance. Stem Cells 33:3581-95
Randolph, Matthew E; Pavlath, Grace K (2015) A muscle stem cell for every muscle: variability of satellite cell biology among different muscle groups. Front Aging Neurosci 7:190
Randolph, Matthew E; Luo, Qingwei; Ho, Justin et al. (2014) Ageing and muscular dystrophy differentially affect murine pharyngeal muscles in a region-dependent manner. J Physiol 592:5301-15
Banerjee, Ayan; Apponi, Luciano H; Pavlath, Grace K et al. (2013) PABPN1: molecular function and muscle disease. FEBS J 280:4230-50
Apponi, Luciano H; Corbett, Anita H; Pavlath, Grace K (2013) Control of mRNA stability contributes to low levels of nuclear poly(A) binding protein 1 (PABPN1) in skeletal muscle. Skelet Muscle 3:23
Apponi, Luciano H; Corbett, Anita H; Pavlath, Grace K (2011) RNA-binding proteins and gene regulation in myogenesis. Trends Pharmacol Sci 32:652-8