The School of Hard Knocks

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Science  30 May 2008:
Vol. 320, Issue 5880, pp. 1134-1135
DOI: 10.1126/science.320.5880.1134c

The identification of a disease-causing gene mutation in humans is typically followed by a flurry of research aimed at elucidating the normal function of the gene and how disruption of that function produces the specific pathological features of the disease. These projects often rely on the phenotypic characterization of mice in which the murine ortholog of the gene has been inactivated (knock-out mice) or in which the specific disease-causing mutation has been introduced into the murine germline (knock-in mice).

Although such models are informative, a recent analysis serves as a reminder that mice are not men, especially when it comes to protein quality-control systems. By examining the Mouse Genome Informatics database and the literature, Liao and Zhang identified 120 genes known to be essential for human survival and found that 22% of these are nonessential in mice. Interestingly, nearly half of these 27 genes encode proteins localized to vacuoles, which are membrane-bound compartments that help remove cellular waste such as misfolded proteins. In independent studies, Kobuke et al. and Bartoli et al. found that a missense mutation responsible for a specific type of muscular dystrophy in humans (an R77C substitution in alpha-sarcoglycan) caused no disease phenotype when introduced into mice. In this case also, the cross-species difference was tentatively traced to the quality-control systems that recognize and process defective proteins. — PAK

Proc. Natl. Acad. Sci. U.S.A. 105, 6987 (2008); Hum. Mol. Genet. 17, 1201; 1214 (2008).

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