PABPN1 loss-of-function in oculopharyngeal muscular dystrophy primarily impacts APA-shift in muscle transcripts

Alternative polyadenylation (APA) at the 3’UTR of transcripts contributes to the cell transcriptome. APA is suppressed by the nuclear RNA binding protein, PABPN1. Aging-associated reduced PABPN1 levels in skeletal muscles lead to muscle wasting. Muscle weakness in oculopharyngeal muscular dystrophy (OPMD) is caused by short alanine expansion in PABPN1 exon1. The expanded PABPN1 forms nuclear aggregates, an OPMD hallmark. Whether the expanded PABPN1 affect APA and how contributes to muscle pathology is unresolved. To investigate these questions, we developed a procedure including RNA library preparation and a simple pipeline calculating ‘APA-shift’ ratio as a readout for PABPN1 function. Using the mouse OPMD model we demonstrate similar results between previously published PAS utilization and ‘APA-shift’ results. Studying APA-shift in two OPMD models and in OPMD patients we show that the expression of the expanded PABPN1 does not correlate with APA-shift. Instead, APA-shift is correlated with reduced expression levels of PABPN1 isoforms, amongst the isoform lacking exon1. Further we show that with our protocol APA-shift is enriched in muscle transcripts, moreover in OPMD patients. We suggest that muscle weakness in OPMD is caused by PABPN1 loss-of-function leading to APA-shift that primarily affects in muscle transcripts. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study did not receive any funding ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study has used human samples. All participants signed informed consent and muscle collection was approved by the Radboud medical ethics board (CMO No. NL54606.091.15). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors