TY - JOUR
T1 - Gene expression profiling in pachyonychia congenita skin
AU - Cao, Yu An
AU - Hickerson, Robyn P.
AU - Seegmiller, Brandon L.
AU - Grapov, Dmitry
AU - Gross, Maren M.
AU - Bessette, Marc R.
AU - Phinney, Brett S.
AU - Flores, Manuel A.
AU - Speaker, Tycho J.
AU - Vermeulen, Annaleen
AU - Bravo, Albert A.
AU - Bruckner, Anna L.
AU - Milstone, Leonard M.
AU - Schwartz, Mary E.
AU - Rice, Robert H.
AU - Kaspar, Roger L.
PY - 2015/3
Y1 - 2015/3
N2 - 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.
AB - 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.
KW - Desquamation
KW - Genodermatosis
KW - Keratinocyte
KW - Monogenic skin disorder
KW - MTOR signaling pathway
KW - Painful palmoplantar keratoderma
UR - http://www.scopus.com/inward/record.url?scp=84925326530&partnerID=8YFLogxK
U2 - 10.1016/j.jdermsci.2015.01.001
DO - 10.1016/j.jdermsci.2015.01.001
M3 - Article
C2 - 25656049
AN - SCOPUS:84925326530
SN - 0923-1811
VL - 77
SP - 156
EP - 165
JO - Journal of Dermatological Science
JF - Journal of Dermatological Science
IS - 3
ER -