TY - JOUR
T1 - Keratin 16-null mice develop palmoplantar keratoderma, a hallmark feature of pachyonychia congenita and related disorders
AU - Lessard, Juliane C.
AU - Coulombe, Pierre A.
N1 - Funding Information:
C57 Bl/6 ES cells in which the Krt16 coding sequence has been replaced with a lacZ-loxP-Neo R -loxP cassette were created by Velocigene using funds provided by the trans-NIH KOMP (Knock-Out Mouse Project), and obtained from the KOMP repository (supported by the NCRR-NIH). ES cells were injected into C57 Bl/6 cBrd/cBrd albino blastocysts (distributed by the NCI, Frederick, MD). A high coat color male chimera was bred to C57 Bl/6 cBrd/cBrd albino females and 100% germline transmission was observed. Krt16 +/− F1 offspring were born at the expected 50:50 ratio and inter-crossed to generate Krt16 −/− mice. All experiments involving mice were reviewed and approved by the Johns Hopkins Institutional Animal Care and Use Committee. Mouse lines were maintained under specific pathogen-free conditions, and fed chow and water ad libitum. All experiments were performed using littermate controls (wild-type or Krt16 +/− ).
Funding Information:
We thank Dr Michael Caterina for help with the behavioral assays, Janet Folmer for assistance with electron microscopy, Renee Araiza at KOMP, and members of the Coulombe lab for their discussion and critical reading of the manuscript. These studies were supported by grant AR44232 to PAC from the National Institute of Arthritis, Musculoskeletal, and Skin Diseases (NIAMS) at the National Institutes of Health.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2012/5
Y1 - 2012/5
N2 - Keratin 16 (KRT16 in human, Krt16 in mouse), a type I intermediate filament protein, is constitutively expressed in epithelial appendages and is induced in the epidermis upon wounding and other stressors. Mutations altering the coding sequence of KRT16 cause pachyonychia congenita (PC), a rare autosomal dominant disorder characterized by hypertrophic nail dystrophy, oral leukokeratosis, and palmoplantar keratoderma (PPK). PPK associated with PC is extremely painful and compromises patient mobility, making it the most debilitating PC symptom. In this study, we show that, although inherited in a recessive manner, the inactivation of Krt16 in mice consistently causes oral lesions as well as PPK-like hyperkeratotic calluses on Krt16-/- front and hind paws, which severely compromise the animals' ability to walk. Our findings call into question the view that PC-related PPK arises exclusively as a gain-of-function on account of dominantly acting mutated keratins, and highlight the key role of modifiers in the clinical heterogeneity of PC symptoms.
AB - Keratin 16 (KRT16 in human, Krt16 in mouse), a type I intermediate filament protein, is constitutively expressed in epithelial appendages and is induced in the epidermis upon wounding and other stressors. Mutations altering the coding sequence of KRT16 cause pachyonychia congenita (PC), a rare autosomal dominant disorder characterized by hypertrophic nail dystrophy, oral leukokeratosis, and palmoplantar keratoderma (PPK). PPK associated with PC is extremely painful and compromises patient mobility, making it the most debilitating PC symptom. In this study, we show that, although inherited in a recessive manner, the inactivation of Krt16 in mice consistently causes oral lesions as well as PPK-like hyperkeratotic calluses on Krt16-/- front and hind paws, which severely compromise the animals' ability to walk. Our findings call into question the view that PC-related PPK arises exclusively as a gain-of-function on account of dominantly acting mutated keratins, and highlight the key role of modifiers in the clinical heterogeneity of PC symptoms.
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U2 - 10.1038/jid.2012.6
DO - 10.1038/jid.2012.6
M3 - Article
C2 - 22336941
AN - SCOPUS:84859785430
VL - 132
SP - 1384
EP - 1391
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
SN - 0022-202X
IS - 5
ER -