A potential animal model for studying CF heterozygote advantage: Genetic variation in theophylline-inducible colonic chloride currents among inbred strains of mice

Sweet, Ann M.; Erickson, Robert P.; Huntington, Caleb; Dawson, David C.

doi:10.1016/0885-4505(92)90011-m

Cited by 4 publications

(2 citation statements)

References 25 publications

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“…Interestingly, the most severe phenotypes, including death at 3 months of age, were observed in the mixed 129/Sv-CD-1 animals, indicating the existence of important modifying alleles in the outbred CD-1 strain. The influence of the genetic background on the phenotypes has been reported in knockout mouse models of several human diseases, including cystic fibrosis and Huntington disease [20], [21], [22]. Furthermore, in some cases those animals have been successfully used for the identification of the respective genetic modifier [23], [24], [25].…”

Section: Discussionmentioning

confidence: 99%

A New Mouse Model for Marfan Syndrome Presents Phenotypic Variability Associated with the Genetic Background and Overall Levels of Fbn1 Expression

et al. 2010

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Marfan syndrome is an autosomal dominant disease of connective tissue caused by mutations in the fibrillin-1 encoding gene FBN1. Patients present cardiovascular, ocular and skeletal manifestations, and although being fully penetrant, MFS is characterized by a wide clinical variability both within and between families. Here we describe a new mouse model of MFS that recapitulates the clinical heterogeneity of the syndrome in humans. Heterozygotes for the mutant Fbn1 allele mgΔloxPneo, carrying the same internal deletion of exons 19–24 as the mgΔ mouse model, present defective microfibrillar deposition, emphysema, deterioration of aortic wall and kyphosis. However, the onset of a clinical phenotypes is earlier in the 129/Sv than in C57BL/6 background, indicating the existence of genetic modifiers of MFS between these two mouse strains. In addition, we characterized a wide clinical variability within the 129/Sv congenic heterozygotes, suggesting involvement of epigenetic factors in disease severity. Finally, we show a strong negative correlation between overall levels of Fbn1 expression and the severity of the phenotypes, corroborating the suggested protective role of normal fibrillin-1 in MFS pathogenesis, and supporting the development of therapies based on increasing Fbn1 expression.

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Section: Discussionmentioning

confidence: 99%

A New Mouse Model for Marfan Syndrome Presents Phenotypic Variability Associated with the Genetic Background and Overall Levels of Fbn1 Expression

et al. 2010

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“…Although called "genetic disease," they are also the consequence of interactions between the defected gene(s), and other genes, and also the environment, that is why so many of animal models failed to mimic phenotype of genetic disorders; for example, cystic fibrosis (CF) transgenic mice failed to mimic pancreas blockage and lung infections that happen in humans with CF [60,61].…”

Section: Genetic Diseasesmentioning

confidence: 99%

Inappropriate modeling of chronic and complex disorders: How to reconsider the approach in the context of predictive, preventive and personalized medicine, and translational medicine

Seifirad

Haghpanah

2019

EPMA Journal

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Preclinical investigations such as animal modeling make the basis of clinical investigations and subsequently patient care. Predictive, preventive, and personalized medicine (PPPM) not only highlights a patient-tailored approach by choosing the right medication, the right dose at the right time point but it as well essentially requires early identification, by the means of complex and state-of-the-art technologies of unmanifested pathological processes in an individual, in order to deliver targeted prevention early enough to reverse manifestation of a pathology. Such an approach can be achieved by taking into account clinical, pathological, environmental, and psychosocial characteristics of the patients or an individual who has a suboptimal health condition. Inappropriate modeling of chronic and complex disorders, in this context, may diminish the predictive potential and slow down the development of PPPM and consequently modern healthcare. Therefore, it is the common goal of PPPM and translational medicine to find the solution for the problem we present in our review. Both, translational medicine and PPPM in parallel, essentially need accurate surrogates for misleading animal models. This study was therefore undertaken to provide shreds of evidence against the validity of animal models. Limitations of current animal models and drug development strategies based on animal modeling have been systematically discussed. Finally, a variety of potential surrogates have been suggested to change the unfavorable situation in medical research and consequently in healthcare.

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Mouse models of human genetic disease: Which mouse is more like a man?

Erickson¹

1996

BioEssays

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There has always been great interest in animal models of human genetic disease, and mice provide the largest number of examples. A mutation in the homologous gene in mice does not always lead to the same phenotype as is found in man, however. Recent studies made it apparent that one mutation can have markedly different phenotypes when placed on different genetic backgrounds. This variation is due to different alleles at modifying loci in various inbred strains. Thus, if one wishes to obtain the optimal mouse model for a human disease, one needs to choose the correct genetic background as well as the correct mutation.

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A potential animal model for studying CF heterozygote advantage: Genetic variation in theophylline-inducible colonic chloride currents among inbred strains of mice

Cited by 4 publications

References 25 publications

A New Mouse Model for Marfan Syndrome Presents Phenotypic Variability Associated with the Genetic Background and Overall Levels of Fbn1 Expression

A New Mouse Model for Marfan Syndrome Presents Phenotypic Variability Associated with the Genetic Background and Overall Levels of Fbn1 Expression

Inappropriate modeling of chronic and complex disorders: How to reconsider the approach in the context of predictive, preventive and personalized medicine, and translational medicine

Mouse models of human genetic disease: Which mouse is more like a man?

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