The “Nihon” model of renal cell carcinoma (RCC) was found in a Sprague-Dawley strain of rats (Okimoto et al., 2004). These rats contain a single nucleotide insertion within exon 3 of FLCN (c.462_463insC), producing a frameshift and premature stop codon within the gene. The homozygous mutant is lethal at an early stage of embryonic development. However, in heterozygotes, renal carcinomas develop from pre-neoplastic lesions as early as three weeks post-partum, then into adenomas by eight weeks post-partum, with all rats presenting with symptoms by six months. The renal carcinomas that develop in heterozygotes are largely composed of clear cells. Loss of heterozygosity at the FLCN locus was observed in ten of eleven primary renal carcinomas examined, supporting the Knudson 2-hit hypothesis (Okimoto et al., 2004).
Further characterisation of the Nihon rat was conducted by Kouchi et al. (2006), where they described the extra-renal lesions seen in the endometrium, salivary glands and cardiac tissue of this model. Rescue experiments demonstrated that re-introduction of the FLCN gene could rescue the embryonic lethality of the homozygous mutants, as well as suppress the renal carcinogenesis seen in heterozygous rats (Togashi et al., 2006).
Contact information regarding this model can be found in: Lab essentials – BHD Animal Models