Abstract
A spontaneously arising, loss-of-function mutation in the RNA binding motif protein 20 (Rbm20) gene, which encodes a nuclear splicing protein, was previously identified as the underlying reason for expression of an abnormally large TITIN (TTN) protein in a rat model of cardiomyopathy. An outbreak of Pseudomonas aeruginosa led to submission of rats with dyspnea, sneezing, lethargy, nasal discharge, and/or unexpected death for diagnostic evaluation. Necropsy revealed underlying megaesophagus in Rbm20–/– rats. Further phenotyping of this rat strain and determination of the size of esophageal TTN was undertaken. The Rbm20-defective rats developed megaesophagus at an early age (26 weeks) with high frequency (13/32, 41%). They also often exhibited secondary rhinitis (9/32, 28%), aspiration pneumonia (8/32, 25%), and otitis media/interna (6/32, 19%). In addition, these rats had a high prevalence of hydronephrosis (13/32, 41%). RBM20 is involved in splicing multiple RNA transcripts, one of which is the muscle-specific protein TTN. Rbm20 mutations are a significant cause of dilated cardiomyopathy in humans. In Rbm20-defective rats, TTN size was significantly increased in the skeletal muscle of the esophagus. Megaesophagus in this rat strain (maintained on a mixed genetic background) is hypothesized to result from altered TTN stretch signaling in esophageal skeletal muscle. This study describes a novel mechanism for the development of megaesophagus, which may be useful for understanding the pathogenesis of megaesophagus in humans and offers insights into potential myogenic causes of this condition. This is the first report of megaesophagus and other noncardiac pathogenic changes associated with mutation of Rbm20 in any species.
Highlights
A spontaneously arising, loss-of-function mutation in the RNA binding motif protein 20 (Rbm20) gene, which encodes a nuclear splicing protein, was previously identified as the underlying reason for expression of an abnormally large TITIN (TTN) protein in a rat model of cardiomyopathy
The middle ear contains viable and degenerate neutrophils admixed with macrophages, surrounding intralesional foreign material (a) that is birefringent under polarized light (b, arrow), indicating plant origin
There was a close relationship between the presence of megaesophagus, aspiration pneumonia, rhinitis, otitis media, and clinical signs such as dyspnea, sneezing, and nasal discharge
Summary
A spontaneously arising, loss-of-function mutation in the RNA binding motif protein 20 (Rbm20) gene, which encodes a nuclear splicing protein, was previously identified as the underlying reason for expression of an abnormally large TITIN (TTN) protein in a rat model of cardiomyopathy. The Rbm20defective rats developed megaesophagus at an early age (26 weeks) with high frequency (13/32, 41%) They often exhibited secondary rhinitis (9/32, 28%), aspiration pneumonia (8/32, 25%), and otitis media/interna (6/32, 19%). This study describes a novel mechanism for the development of megaesophagus, which may be useful for understanding the pathogenesis of megaesophagus in humans and offers insights into potential myogenic causes of this condition This is the first report of megaesophagus and other noncardiac pathogenic changes associated with mutation of Rbm[20] in any species. Chemical models of megaesophagus use benzalkonium chloride, which denervates the esophagus, causing achalasia, megaesophagus, hypertrophy of the muscularis, and increased epithelial proliferation in rats.[8]
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