Letter to the Editor

Editor:

Necropsy (autopsy for humans) procedures with histopathologic evaluation of tissues are fundamentally the same regardless of species. Inbred laboratory mice present an additional challenge with interpretation of lesions associated or thought to be associated with a mutated gene. Strain specific background lesions are scattered in the literature and in mouse specific pathology books ⁴ , ⁵ , ⁷ , ⁸ , ¹² but soon will be available on the World Wide Web (http://tumor.informatics.jax.org). These resources are starting points for obtaining information on strain specific lesions but fail to account for husbandry variations between colonies, different substrains of mice, and many other factors that vary between institutions resulting in changes in frequency and types of disease in an inbred strain of mice.

Several years ago a description of epicardial and corneal mineralization in in C.B-17 scid/scid (severe combined immunodeficiency) mice was published in Veterinary Pathology. ⁶ The authors attributed the lesions to the severe combined immunodeficiency (scid) mutation. Although well done as a pathological workup, no C.B-17 +/+ (normal wildtype control mice) or C.B-17 +/scid (normal heterozygous control mice since this is an autosomal recessive mutation) were included in the study. Had the authors checked these control mice they would have found identical changes. Furthermore, presence or absence and distribution patterns of cardiac mineralization and fibrosis are identical in scid/scid, +/+, and +/scid mice based on the congenic backgrounds the mutant gene has been transferred onto. Cardiac calcinosis is due to polymorphisms/mutations in other genes, not scid. Pulmonary mineralization (“pulmonary alveolar microlithiasis in nackt mice”) in a recent Veterinary Pathology issue ⁹ and bone density ¹ , ² are other manifestations of this disease process.

The recent paper in Veterinary Pathology on pulmonary alveolar microlithiasis in nackt mice identified lesions in 4 mutant mice on an undefined congenic background while no such lesions were found in two presumably outbred SENCAR mice (SENCARB/PtJ and SENCARC/PtJ are inbred strains derived from outbred SENCAR mice; http://jaxmice.jax.org/html/infosearch/pricelistframeset.html). No attempt to clearly define strain or genotype is provided. Although the symbol nackt was used in the paper, the official gene symbol is Ctsl ^nkt (http://www.informatics.jax.org/searches/marker.cgi?1252). Furthermore, three allelic mutations exist (Ctsl ^fs , Ctsl ^nkt , and Ctsl ^tm1Cptr ). A simple study to define the role of cathepsin L, the gene mutated in nackt mice, would be to look at mutant and control mice from all three allelic mutations. This would be further optimized if all three allelic mutations were on the same inbred/congenic background. If lesions are present in mutants but not age and gender matched controls then the conclusions in the current paper are correct. Comparison to unrelated strains in the same colony are not appropriate controls. Failure to use internationally accepted nomenclature for inbred strains and mutations makes it impossible to understand the experimental design in this report.

The value of inbred laboratory mice with single gene mutations, especially when multiple allelic mutations are available, is that routine, carefully done gross and histopathology, often not done in the original workups, can yield a great deal of useful and often novel information. Approaches to selection of controls, ¹¹ and general protocols are available. ³ , ¹⁰ , ¹² Working with mutant mice is not that different from other species but the level of sophistication required is much higher because of access to environmentally and microbiologically controlled colonies, numerous animals, and good controls based on access to genetically defined mice.

Sincerely,