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J. Biol. Chem., Vol. 283, Issue 24, 16868-16875, June 13, 2008

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

Naoki Nanashima, Miki Akita^¶, Toshiyuki Yamada, Takeshi Shimizu, Hajime Nakano^¶, Yang Fan, and Shigeki Tsuchida¹

From the Department of Biochemistry and Genome Biology, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, the Department of Biomedical Sciences, Hirosaki University Graduate School of Health Sciences, Hirosaki 036-8564, and the ^¶Department of Dermatology, Hirosaki University Graduate School of Medicine, Hirosaki 036-8562, Japan

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 wild-type 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.

Received for publication, April 2, 2008 , and in revised form, April 16, 2008.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AB354637 [GenBank] , AB355638 [GenBank] , and AB355639.

^* This work was supported in part by grants-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and from the Food Safety Commission of Japan and by grants from Hirosaki University School of Medicine and the Hirosaki Foundation for Science and International Exchange. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 81-172-39-5018; Fax: 81-172-39-5205; E-mail: tsuchida{at}cc.hirosaki-u.ac.jp.

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