The Complexity of Disease Phenotypes
Animal models have been invaluable in understanding how gene mutations physically affect a complex organism. However, as vividly illustrated in a new research study examining mice with a metabolic disease, the same mutation in the same species can produce wildly variable results.
Niemann-Pick type C (NPC) disease is a rare genetic condition brought on by a mutation in one protein, NPC1, which helps shuttle cholesterol out of a cell compartment called the lysosome. As a result, cholesterol accumulates in virtually every tissue in the body, causing widespread organ dysfunction and death.
John Dietschy and colleagues evaluated how factors like genetic background, additional mutations, and environmental influences affected the lifespan of a mouse model of NBC. Overall, the lifespan of different npc1–/– mice ranged from 50-130 days, and even simple differences such as the host colony (same strain, just different location of breeding), or slight alterations in diet affected the average lifespan.
These studies highlight just how complex a ‘simple’ genetic disease really is, and that such variability should be carefully considered when designing animal experiments or interpreting results. It is particularly important, Dietschy and colleagues note, to use these animal models to carefully differentiate the non-specific environmental and genetic effects on lifespan from treatments that have a direct effect on the genetic abnormality present in the disease and thus may promote survival.
Corresponding Author: John M. Dietschy, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX; Phone: 214-648-2150; email: firstname.lastname@example.org
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