The Hairless Phenotype of the Hirosaki Hairless Rat Is Due to the Deletion of an 80-kb Genomic DNA Containing Five Basic Keratin Genes

Abstract

Most models of hereditary hypotrichosis are due to alterations in growth factors and transcription factors, and the examples of causative mutations in hair keratin genes are limited. The Hirosaki hairless rat (HHR) is a mutant strain spontaneously derived from Sprague-Dawley rats (SDRs). In this study, the locus of the responsible gene was examined by linkage analysis and mapped on chromosome 7q36. Because many basic keratin genes are clustered on 7q36, their expression was examined. Reverse transcription-PCR and genomic PCR indicated that the Kb21 (Krt81), -23 (Krt83), and -26 (Krt86) genes encoding basic hair keratins were not expressed and were deleted. Furthermore, 80-kb genomic DNA ranging from exon 9 of Kb25 (Krt85) to exon 9 of Krt2-25 was deleted. The breakpoints of these genes were within a 95-bp portion shared by the two genes, suggesting that deletion due to non-allelic homologous recombination occurred. Proteins identified as Kb21, Kb23, and Krt2-25 in SDR hairs by mass spectrometry were not detected in HHR. Instead, the product of a fusion gene became dominant in HHR. Because fusion occurred between the exons of the two genes with the same sequences, the product was identical to the wildtype Kb25 protein. By using immunohistochemistry, Kb21 was not detected in HHR hair follicles. Kb25 was expressed in the cortex in HHRs, whereas it was in the medulla in SDRs. This study clearly illustrates the importance of hair keratin genes in hair growth.The large keratin multigene family comprises cytokeratins, which are differentially expressed in the various types of epithelia, and hair keratins, expressed in hard keratinized structures such as hairs, nails, and claws. These keratins can be divided into the acidic type I and the basic-to-neutral type II members, which form the 10 nm intermediate filament network through the obligatory association of equimolar amounts of type I and type II keratins (1). Previous studies on the hair keratins of several mammals reveal the presence of nine type I and six type II members (1, 2). Hair keratins are collectively designated "H" for hair, "b" for the basic members (Hb), and "a" for the acidic members (Ha) (3). In the case of rats, genes encoding the basic members are designated Kb21-26. In rats, the type I keratin genes are clustered on chromosome 10q31 and the type II gene cluster on 7q36 (4). The latter cluster includes Kb21-26 on a DNA domain of ϳ200 kb.Hairs are produced in hair follicles. The hair follicle includes not only the cortex and medulla but also the inner root sheath, companion layer, and outer root sheath (5). Recent studies have revealed that some specific cytokeratins are expressed in the inner root sheath (6) and other components (4, 7). Numerous growth factors and cytokines such as Wnt (8, 9) and transforming growth factor (10, 11) are involved in hair follicle formation, and mutations of these genes cause various types of hypotrichosis. Furthermore, loss-of-function mutation of the transcription factor Foxn1 is responsible for the nude phenotype (12...

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PERP regulates enamel formation via effects on cell–cell adhesion and gene expression

“…Mutations in Krt83 have been associated with monilethrix, an autosomal hair disorder that can cause scarring alopecia (Carreras, 1996;van Steensel et al, 2005), and the hairless phenotype of the Hirosaki hairless rat (Nanashima et al, 2008). Hair keratins, and in particular Krt83, have yet to be studied in teeth.…”

Lectin-like Receptor Ly49s3 on Dendritic Cells Contributes to the Differentiation of Regulatory T Cells in the Rat Thymus

“…In these animals, mutations in the Foxn1 gene are responsible for both the immunodeficiency and the hairless phenotype because Foxn1 is a critical transcription factor for the differentiation and survival of both thymic and skin epithelial cells (14,15). In HHRs, we demonstrated a deletion of 80 kb of genomic DNA containing five basic keratin genes as the reason for the hairless phenotype (16). However, it remains to be determined whether the HHR possesses other genetic abnormalities or exhibits deficiencies in its immune system.…”

“…We have demonstrated the deletion of 80 kb of genomic DNA containing five basic keratin genes in HHRs as the reason for their hairless phenotype (16). The similarity of loci for basic keratin genes and Ly49 genes involves the clustering of genes showing sequence homologies.…”