Very mild disease phenotype of congenic Cftr super()TgH(neoim)Hgu ystic fibrosis mice

Background A major boost to cystic fibrosis disease research was given by the generation of various mouse models using gene targeting in embryonal stem cells. Moreover, the introduction of the same mutation on different inbred strains generating congenic strains facilitated the search for modifier genes. From the original Cftr super()TgH(neoim)Hgu ouse model with a divergent genetic background (129/Sv, C57BL/6, HsdOla:MF1) two inbred mutant mouse strains CF/1-Cftr super()TgH(neoim)Hgu nd CF/3-Cftr super()TgH(neoim)Hgu ad been generated using strict brother sister mating. CF/1-Cftr super()TgH(neoim)Hgu nd CF/3-Cftr super()TgH(neoim)Hgu ice were fertile and showed normal growth and lifespan. In this work the Cftr super()TgH(neoim)Hgu nsertional mutation was backcrossed from CF/3-CftruTgH(neoim)Hgu nto the inbred backgrounds C57BL/6J and DBA/2J generating congenic animals in order to clarify the differential impact of the Cftr mutation and the genetic background on the disease phenotype of the cystic fibrosis mutant mice. Clinical and electrophysiological features of the two congenic strains were compared with those of CF/1-Cftr super()TgH(neoim)Hgu nd CF/3-Cftr super()TgH(neoim)Hgu nd wild type controls. Results Under the standardized housing conditions of the animal facility, the four mouse strains CF/1-Cftr super()TgH(neoim)Hgu, CF/3-Cftr super()TgH(neoim)Hgu, D2.129P2(CF/3)-Cftr super()TgH(neoim)Hgu nd B6.129P2(CF/3)-Cftr super()TgH(neoim)Hgu xhibited normal life expectancy. Growth of congenic cystic fibrosis mice was comparable with that of wild type controls. All mice but D2.129P2(CF/3)-Cftr super()TgH(neoim)Hgu emales were fertile. Short circuit current measurements revealed characteristic response profiles of the HsdOla:MF1, DBA/2J and C57BL/6J backgrounds in nose, ileum and colon. All cystic fibrosis mouse lines showed the disease-typical hyperresponsiveness to amiloride in the respiratory epithelium. The mean chloride secretory responses to carbachol or forskolin were 15-100% of those of the cognate wild type control animals. Conclusion The amelioration of the clinical features and of the basic defect that had emerged during the generation of CF/3-Cftr super()TgH(neoim)Hgu ice was retained in the congenic mice indicating that the Cftr linkage group or other loci shared between the inbred strains contain(s) the major modifier(s) of attenuation of cystic fibrosis symptoms.