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Molecular and Cellular Biology, January 2005, p. 197-205, Vol. 25, No. 1
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.1.197-205.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Overcoming Functional Redundancy To Elicit Pachyonychia Congenita-Like Nail Lesions in Transgenic Mice

Pauline Wong,¹ Renee Domergue,² and Pierre A. Coulombe^1,3*

Departments of Biological Chemistry,¹ Dermatology,³ Graduate Training Program in Cellular and Molecular Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland²

Received 24 May 2004/ Returned for modification 7 July 2004/ Accepted 20 September 2004

Mutations affecting the coding sequence of intermediate filament (IF) proteins account for >30 disorders, including numerous skin bullous diseases, myopathies, neuropathies, and even progeria. The manipulation of IF genes in mice has been widely successful for modeling key features of such clinically distinct disorders. A notable exception is pachyonychia congenita (PC), a disorder in which the nail and other epithelial appendages are profoundly aberrant. Most cases of PC are due to mutations in one of the following keratin-encoding genes: K6, K16, and K17. Yet null alleles obliterating the function of both K6 genes (K6 and K6ß) or the K17 gene, as well as the targeted expression of a dominant-negative K6 mutant, elicit only a subset of PC-specific epithelial lesions (excluding that of the nail in mice). We show that newborn mice null for K6, K6ß, and K17 exhibit severe lysis restricted to the nail bed epithelium, where all three genes are robustly expressed, providing strong evidence that this region of the nail unit is initially targeted in PC. Our findings point to significant redundancy among the multiple keratins expressed in hair and nail, which can be related to the common ancestry, clustered organization, and sequence relatedness of specific keratin genes.

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* Corresponding author. Mailing address: Department of Biological Chemistry, Johns Hopkins University School of Medicine, 725 North Wolfe St., Baltimore, MD 21205. Phone: (410) 614-0510. Fax: (410) 614-7567. E-mail: coulombe{at}jhmi.edu.

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Molecular and Cellular Biology, January 2005, p. 197-205, Vol. 25, No. 1
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.1.197-205.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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