Mouse Genome Informatics
hm
    Cftrtm1Unc/Cftrtm1Unc
B6.129P2-Cftrtm1Unc/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       

Pancreatic morphology and morphometry of Cftrtm1Unc/Cftrtm1Unc mice

homeostasis/metabolism
N
• although mutant FSH levels are slightly increased relative to wild-type levels, circulating levels of both FSH and LH still remain within normal range at proestrus (J:145380)
• homozygotes exhibit a membrane lipid imbalance characterized by an increase in phospholipid-bound arachidonic acid (AA) and a decrease in phospholipid-bound docosahexaenoic acid (DHA), that is most pronounced in the pancreas, lung and ileum, organs affected in cystic fibrosis, and in the heart
• oral administration of DHA reverses the membrane lipid imbalance

digestive/alimentary system
• massive luminal dilatation
• oral administration of DHA reverses the pancreatic phenotype
• zymogen granule accumulation at the apical pole of the acinar cells
• ileal hypertrophy; villus height is increased
• oral administration of DHA restores villus height to normal
• develop intestinal blockage when fed a normal (solid) diet

respiratory system
• abnormal nasal potential difference
• homozygotes exposed to Pseudomonas LPS daily for 3 days exhibit enhanced lung inflammation, as indicated by a significant increase in neutrophil concentration compared to wild-type (J:58571)
• oral administration of DHA blocks the enhanced neutrophil infiltration in response to Pseudomonas LPS (J:58571)
• increased inflammatory response to chronic Pseudomonas aeruginosa infection (J:112450)

growth/size/body
• reduced at 7, 14, and 21 days of age relative to wild-type mice (J:112450)
• at 6-8 and 14-16 weeks of age, total body weight is reduced by only 15% and 12%, respectively, thus not explaining the larger differences noted in average weight of reproductive organs (~50% and 36%, respectively) (J:145380)

immune system
• homozygotes exposed to Pseudomonas LPS daily for 3 days exhibit enhanced lung inflammation, as indicated by a significant increase in neutrophil concentration compared to wild-type (J:58571)
• oral administration of DHA blocks the enhanced neutrophil infiltration in response to Pseudomonas LPS (J:58571)
• increased inflammatory response to chronic Pseudomonas aeruginosa infection (J:112450)

endocrine/exocrine glands
• massive luminal dilatation
• oral administration of DHA reverses the pancreatic phenotype
• zymogen granule accumulation at the apical pole of the acinar cells
• female homozygotes show an average of 1.5 +/- 2.0 corpora lutea per ovary vs 9.3 +/- 1.4 in wild-type females, even though other follicle stages are present (J:145380)
• at 7 weeks of age, female homozygotes display smaller ovaries than wild-type females (J:145380)
• at 6-8 and 14-16 weeks of age, the average weight of mutant ovaries is reduced by 50% and 36%, respectively, relative to that of wild-type ovaries (J:145380)
• however, mutant ovarian weight is restored to wild-type values after superovulation (J:145380)

reproductive system
• female homozygotes show an average of 1.5 +/- 2.0 corpora lutea per ovary vs 9.3 +/- 1.4 in wild-type females, even though other follicle stages are present (J:145380)
• at 7 weeks of age, female homozygotes display smaller ovaries than wild-type females (J:145380)
• at 6-8 and 14-16 weeks of age, the average weight of mutant ovaries is reduced by 50% and 36%, respectively, relative to that of wild-type ovaries (J:145380)
• however, mutant ovarian weight is restored to wild-type values after superovulation (J:145380)
• only 1 of 15 female homozygotes showed cervical mucus accumulation with no other physical signs of obstruction in the uterus (J:145380)
• at 7 weeks of age, female homozygotes display smaller uteri than wild-type females (J:145380)
• however, no physical signs of obstruction are observed in the uterus (J:145380)
• at 6-8 and 14-16 weeks of age, the average weight of mutant uteri is reduced by 56% and 36%, respectively, relative to that of wild-type uteri (J:145380)
• however, mutant uterus weight is restored to wild-type values after superovulation (J:145380)
• mutant uteri are thinner than wild-type (J:145380)
• female homozygotes display a delayed onset of puberty relative to wild-type controls
• female homozygotes display reduced oocyte ovulation rates relative to wild-type females (J:145380)
• however, normal ovulation rates are observed after superovulation with exogenous hormone (PMSG + hCG) injections (J:145380)
• unlike wild-type females, 41.7% of 14-16-wk-old mutant females never enter estrus but are constantly in diestrus (J:145380)
• at 14-16 weeks of age, female homozygotes that display at least one estrous cycle show half as many cycles as wild-type females, resulting in a 2-fold increase in average cycle length (J:145380)
• female homozygotes exhibit reduced fertility with significantly fewer numbers of litters and smaller litter sizes relative to wild-type females (J:145380)
• 20% of female homozygotes are unable to give birth over a 5-month mating period (J:145380)
• following induction of superovulation, only 1 of 10 mutant females that displayed vaginal plugs gave birth, but that female did give birth to 20 pups (J:145380)
• female homozygotes show a significant decrease in average number of pups per litter relative to wild-type females (3.55 +/- 1.92 vs 6.56 +/- 2.36, respectively)
• at 48 hrs after hCG treatment, 100% of mutant oocytes remain unfertilized, whereas the majority of embryos from superovulated wild-type females are at the 2- to 4-cell stages
• however, no significant differences in in vitro fertilization rates are observed, suggesting that decreased in vivo fertilization is more likely due to inadequate fluid control in the reproductive tract, resulting in decreased sperm number in the oviduct
• sperm transport within the mutant female reproductive system is significantly impaired: the average number of sperm found in mutant oviducts is only ~10% that of wild-type (J:145380)
• however, no differences in capacitation of oviductal sperm from mutant and wild-type females are observed (J:145380)

Mouse Models of Human Disease
OMIM IDRef(s)
Cystic Fibrosis; CF 219700 J:58571 , J:112450