A novel mutation in the nucleoporin NUP35 causes murine degenerative colonic smooth muscle myopathy

Chronic Intestinal Pseudo-Obstruction (CIPO) is a rare, but life-threatening, disease characterized by severe intestinal dysmotility. Histopathological studies of CIPO patients have identified several different mechanisms that appear to be responsible for the dysmotility, including defects in neurons, smooth muscle or interstitial cells of Cajal. Currently there are few mouse models of the various forms of CIPO. We generated a mouse with a point mutation in the RNA Recognition Motif of the Nup35 gene, which encodes a component of the nuclear pore complex. Nup35 mutants developed a severe megacolon and exhibited reduced lifespan. Histopathological examination revealed a degenerative myopathy that developed after birth and specifically affected smooth muscle in the colon; smooth muscle in the small bowel and the bladder were not affected. Furthermore, no defects were found in enteric neurons or interstitial cells of Cajal. Nup35 mice are likely to be a valuable model for the sub-type of CIPO characterized by degenerative myopathy. Our study also raises the possibility that Nup35 polymorphisms could contribute to some cases of CIPO.\n\nSignificance StatementChronic Intestinal Pseudo-Obstruction (CIPO) is a disabling bowel disorder in which the symptoms resemble those caused by mechanical obstruction, but no physical obstruction is present. Some patients with CIPO have defects in intestinal neurons while in other CIPO patients the muscle cells in the bowel wall appear to degenerate, but the underlying cause of these defects is unknown in most CIPO patients. We generated a mouse that has a mutation in Nup35, which encodes a component of the pores found within the membrane of the cell nucleus. The mutant mice developed intestinal obstruction, which we showed was due to degeneration of the muscle cells in the colon. This mouse is likely to provide new insights into some forms of CIPO.