Gene expression profiling in pachyonychia congenita skin

Abstract

Background Pachyonychia congenita (PC) is a skin disorder resulting from mutations in keratin (K) proteins including K6a, K6b, K16, and K17. One of the major symptoms is painful plantar keratoderma. The pathogenic sequelae resulting from the keratin mutations remain unclear. Objective To better understand PC pathogenesis. Methods RNA profiling was performed on biopsies taken from PC-involved and uninvolved plantar skin of seven genotyped PC patients (two K6a, one K6b, three K16, and one K17) as well as from control volunteers. Protein profiling was generated from tape-stripping samples. Results A comparison of PC-involved skin biopsies to adjacent uninvolved plantar skin identified 112 differentially-expressed mRNAs common to patient groups harboring K6 (i.e., both K6a and K6b) and K16 mutations. Among these mRNAs, 25 encode structural proteins including keratins, small proline-rich and late cornified envelope proteins, 20 are related to metabolism and 16 encode proteases, peptidases, and their inhibitors including kallikrein-related peptidases (KLKs), and serine protease inhibitors (SERPINs). mRNAs were also identified to be differentially expressed only in K6 (81) or K16 (141) patient samples. Furthermore, 13 mRNAs were identified that may be involved in pain including nociception and neuropathy. Protein profiling, comparing three K6a plantar tape-stripping samples to non-PC controls, showed changes in the PC corneocytes similar, but not identical, to the mRNA analysis. Conclusion Many differentially-expressed genes identified in PC-involved skin encode components critical for skin barrier homeostasis including keratinocyte proliferation, differentiation, cornification, and desquamation. The profiling data provide a foundation for unraveling the pathogenesis of PC and identifying targets for developing effective PC therapeutics.

Keratins K2 and K10 are essential for the epidermal integrity of plantar skin

“…S4) may also contribute to the homeostasis of plantar epidermis. Together with previous reports [7,9,[26][27][28], our data suggest that the expression of keratins is subjected to complex regulation and allows for a considerable plasticity in keratin heterodimerization patterns in the epidermis of the sole.…”

Proteomic profiling of Pachyonychia congenita plantar callus

“…They also permit distinguishing the profiles of lamellar ichthyosis from ichthyosis vulgaris and normal epidermis [11]. Initial application to PC, generally supporting findings obtained by DNA microarray, indicate that mutation of KRT6A leads to readily detectable perturbations in levels of several keratins and other proteins [12]. Present work explores the perturbations more generally in plantar epidermis among PC subjects for possible applications to understanding the disease pathogenesis and to assessment of treatment.…”

Sexual Dimorphism in Response to an NRF2 Inducer in a Model for Pachyonychia Congenita

“…Punch biopsies (3 mm) were obtained from individuals with PC with informed written consent as described (Cao et al, 2015), and analyzed for protein expression by immunohistochemistry. Cryosections (50 μm) were cut and incubated with primary antibodies and Alexa Fluor-conjugated secondary antibodies for indirect immunofluorescence (Kerns et al, 2016).…”