Loricrin keratoderma is associated with single nucleotide insertion frame-shift mutations in the loricrin gene. These frame-shift mutations result in addition of a nuclear localization signal to the loricrin protein which causes the loricrin to accumulate in the nucleus where it produces actions that are not understood. The outcome is an extremely debilitating disease of epidermal hyperkeratosis, hyperproliferation, parakeratosis, nuclear loricrin accumulation, and pseudoainhum (autoamputation) of the digits. Mouse studies support a role for mutant loricrin in disease pathogenesis as mutant loricrin-expressing mice display disease features. However, how nuclear loricrin influences events and whether nuclear loricrin is absolutely required for disease pathogenesis is not known. Moreover, our knowledge is very limited regarding how cell signaling is altered in keratoderma. We have developed a novel mouse model wherein we inactivate AP1 transcription factor signaling. The remarkable finding is that these mice display a phenotype that matches the human keratoderma phenotype. This includes epidermal hyperproliferation, hyperkeratosis, parakeratosis, nuclear loricrin accumulation, and tail and digit pseudoainhum. The fact that this appears upon inhibition of AP1 transcription factor function in the suprabasal epidermis, strongly suggests a relationship between nuclear loricrin accumulation, reduced AP1 factor signaling and disease pathogenesis. These mice represent an intriguing opportunity to extend previous discoveries to learn how nuclear loricrin may drive the pathology of keratoderma. We propose a novel hypothesis that nuclear accumulation of loricrin in the epidermal suprabasal layers alters AP1 transcription factor signaling in these cells to drive the disease phenotype.

Public Health Relevance

Loricrin keratoderma is a severe skin disease that is characterized by debilitating changes including increased cell proliferation, epidermal thickening and painful pseudoainhum (autoamputation) of the digits. Our understanding of this disease is extremely limited, except that we know that mutated form of loricrin accumulates in the nucleus and may drive the change in phenotype. We have found that manipulating AP1 factor signaling drives development of a disease in mice that mimic all aspects of human keratoderma. Our goal in this proposal is to characterize these mice to assess whether they are indeed a suitable model for understanding this debilitating family of diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AR065266-01
Application #
8588676
Study Section
Arthritis, Connective Tissue and Skin Study Section (ACTS)
Program Officer
Baker, Carl
Project Start
2013-09-23
Project End
2015-08-31
Budget Start
2013-09-23
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$163,094
Indirect Cost
$56,844
Name
University of Maryland Baltimore
Department
Biochemistry
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Rorke, Ellen A; Adhikary, Gautam; Young, Christina A et al. (2015) Suppressing AP1 factor signaling in the suprabasal epidermis produces a keratoderma phenotype. J Invest Dermatol 135:170-80
Scharadin, Tiffany M; Eckert, Richard L (2014) TIG3: an important regulator of keratinocyte proliferation and survival. J Invest Dermatol 134:1811-6
Saha, Kamalika; Adhikary, Gautam; Kanade, Santosh R et al. (2014) p38? regulates p53 to control p21Cip1 expression in human epidermal keratinocytes. J Biol Chem 289:11443-53