The Charles River "hairless" rat mutation is distinct from the hairless mouse alleles

The Charles River (CR) "hairless" rat is one of the autosomal recessive hypotrichotic animal models actively studied in pharmacologic and dermatologic research. Despite its widespread use, the molecular basis of this monogenic mutation remains unknown, and the skin histologic features of this phenotype have never been described. However, the designation "hairless" has been used as an extension of the hairless mouse (hr) nomenclature on the basis of the clinical absence of hairs in both phenotypes. We present a description of the histopathologic changes in heterozygous and homozygous CR hairless rat mutants during the first month of life. The postnatal homozygous rat skin was characterized by abnormal keratinization of the hair shaft and formation of a thick and dense layer of corneocytes in the lower portion of the epidermal stratum corneum. This layer prevented the improperly keratinized hair shaft from penetrating the skin surface. Starting from the latest stages of hair follicle (HF) development, obvious signs of HF degeneration were observed in homozygous skin. This process was extremely rapid, and by day 12, mainly atrophic HFs with abnormal or broken hairs were present in the skin. Therefore, the mutation in the CR rat abrogates cell proliferation in the hair matrix and affects keratinocyte differentiation in the HF and interfollicular epidermis, a phenotype that is completely distinct from hr/hr. To test whether the CR rat harbored a mutation in the hr gene, we analyzed the coding region of this gene and consensus intron splice site sequences in mutant rats and found no mutation, further supporting phenotypic evidence that the hairless phenotype in CR rats is not allelic with hairless. Finally, using intragenic polymorphisms, we were able to exclude homozygosity at the hairless locus by use of genotypic analysis. Thus, morphologic analysis of successive stages of phenotype development in the CR hairless rat, together with definitive molecular studies, indicate that this mutation may be unique among the other hypotrichotic rat mutations.