title: Very mild disease phenotype of congenic CftrTgH(neoim)Hgu cystic fibrosis mice.
abstract: 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 CftrTgH(neoim)Hgu mouse model with a divergent genetic background (129/Sv, C57BL/6, HsdOla:MF1) two inbred mutant mouse strains CF/1-CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu had been generated using strict brother x sister mating. CF/1-CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu mice were fertile and showed normal growth and lifespan. In this work the CftrTgH(neoim)Hgu insertional mutation was backcrossed from CF/3-CftrTgH(neoim)Hgu onto 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-CftrTgH(neoim)Hgu and CF/3-CftrTgH(neoim)Hgu and wild type controls.
  
  
  RESULTS
  Under the standardized housing conditions of the animal facility, the four mouse strains CF/1-CftrTgH(neoim)Hgu, CF/3-CftrTgH(neoim)Hgu, D2.129P2(CF/3)-CftrTgH(neoim)Hgu and B6.129P2(CF/3)-CftrTgH(neoim)Hgu exhibited normal life expectancy. Growth of congenic cystic fibrosis mice was comparable with that of wild type controls. All mice but D2.129P2(CF/3)-CftrTgH(neoim)Hgu females 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.
  
  
  CONCLUSIONS
  The amelioration of the clinical features and of the basic defect that had emerged during the generation of CF/3-CftrTgH(neoim)Hgu mice 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.
authors.affiliation: Klinische Forschergruppe, OE 6710, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany. balazs_toth@lycos.com
authors.forename: Balázs
authors.initials: B
authors.lastname: Tóth
authors.forename: Martina
authors.initials: M
authors.lastname: Wilke
authors.forename: Frauke
authors.initials: F
authors.lastname: Stanke
authors.forename: Martina
authors.initials: M
authors.lastname: Dorsch
authors.forename: Silke
authors.initials: S
authors.lastname: Jansen
authors.forename: Dirk
authors.initials: D
authors.lastname: Wedekind
authors.forename: Nikoletta
authors.initials: N
authors.lastname: Charizopoulou
authors.forename: Alice
authors.initials: A
authors.lastname: Bot
authors.forename: Marion
authors.initials: M
authors.lastname: Burmester
authors.forename: Sabine
authors.initials: S
authors.lastname: Leonhard-Marek
authors.forename: Hugo R
authors.initials: HR
authors.lastname: de Jonge
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Hedrich
authors.forename: Gerhard
authors.initials: G
authors.lastname: Breves
authors.forename: Burkhard
authors.initials: B
authors.lastname: Tümmler
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight; D002217:Carbachol / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000235:genetics* / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D005298:Fertility; D008040:Genetic Linkage; D005838:Genotype; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D018181:Mice, Inbred CFTR; D018895:Microsatellite Repeats; D010641:Phenotype
chemical_list: D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; D002217:Carbachol