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KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice. | LitMetric

AI Article Synopsis

  • Somatic KRAS mutations are common in different types of cancer, while certain germline KRAS mutations can lead to disorders called RASopathies.
  • Researchers created special mice with two different KRAS mutations to study their effects on development and health.
  • The study found that one mutation (KrasT58I) caused facial problems and organ growth issues, while another (KrasP34R) led to breathing problems that resulted in early death, showing that these mutations affect the body in different ways.

Article Abstract

Somatic KRAS mutations are highly prevalent in many cancers. In addition, a distinct spectrum of germline KRAS mutations causes developmental disorders called RASopathies. The mutant proteins encoded by these germline KRAS mutations are less biochemically and functionally activated than those in cancer. We generated mice harboring conditional KrasLSL-P34Rand KrasLSL-T58I knock-in alleles and characterized the consequences of each mutation in vivo. Embryonic expression of KrasT58I resulted in craniofacial abnormalities reminiscent of those seen in RASopathy disorders, and these mice exhibited hyperplastic growth of multiple organs, modest alterations in cardiac valvulogenesis, myocardial hypertrophy, and myeloproliferation. By contrast, embryonic KrasP34R expression resulted in early perinatal lethality from respiratory failure due to defective lung sacculation, which was associated with aberrant ERK activity in lung epithelial cells. Somatic Mx1-Cre-mediated activation in the hematopoietic compartment showed that KrasP34R and KrasT58I expression had distinct signaling effects, despite causing a similar spectrum of hematologic diseases. These potentially novel strains are robust models for investigating the consequences of expressing endogenous levels of hyperactive K-Ras in different developing and adult tissues, for comparing how oncogenic and germline K-Ras proteins perturb signaling networks and cell fate decisions, and for performing preclinical therapeutic trials.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710308PMC
http://dx.doi.org/10.1172/jci.insight.140495DOI Listing

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