Altered keratinocyte differentiation is an early driver of keratin mutation-based palmoplantar keratoderma

Hum Mol Genet. 2019 Jul 1;28(13):2255-2270. doi: 10.1093/hmg/ddz050.

Abstract

The type I intermediate filament keratin 16 (KRT16 gene; K16 protein) is constitutively expressed in ectoderm-derived appendages and in palmar/plantar epidermis and is robustly induced when the epidermis experiences chemical, mechanical or environmental stress. Missense mutations at the KRT16 locus can cause pachyonychia congenita (PC, OMIM:167200) or focal non-epidermolytic palmoplantar keratoderma (FNEPPK, OMIM:613000), which each entail painful calluses on palmar and plantar skin. Krt16-null mice develop footpad lesions that mimic PC-associated PPK, providing an opportunity to decipher its pathophysiology, and develop therapies. We report on insight gained from a genome-wide analysis of gene expression in PPK-like lesions of Krt16-null mice. Comparison of this data set with publicly available microarray data of PPK lesions from individuals with PC revealed significant synergies in gene expression profiles. Keratin 9 (Krt9/K9), the most robustly expressed gene in differentiating volar keratinocytes, is markedly downregulated in Krt16-null paw skin, well-ahead of lesion onset, and is paralleled by pleiotropic defects in terminal differentiation. Effective prevention of PPK-like lesions in Krt16-null paw skin (via topical delivery of the Nrf2 inducer sulforaphane) involves the stimulation of Krt9 expression. These findings highlight a role for defective terminal differentiation and loss of Krt9/K9 expression as additional drivers of PC-associated PPK and highlight restoration of KRT9 expression as a worthy target for therapy. Further, we report on the novel observation that keratin 16 can localize to the nucleus of epithelial cells, implying a potential nuclear function that may be relevant to PC and FNEPPK.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Differentiation
  • Dermis / drug effects
  • Dermis / physiopathology
  • HeLa Cells
  • Humans
  • Interleukin-1 / genetics
  • Interleukin-1 / metabolism
  • Isothiocyanates / therapeutic use
  • Kelch-Like ECH-Associated Protein 1 / metabolism
  • Keratin-16 / genetics*
  • Keratin-16 / metabolism
  • Keratin-9 / genetics
  • Keratin-9 / metabolism*
  • Keratinocytes / cytology*
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Keratins / metabolism
  • Keratoderma, Palmoplantar / drug therapy
  • Keratoderma, Palmoplantar / etiology
  • Keratoderma, Palmoplantar / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Mutation, Missense
  • NF-E2-Related Factor 2 / metabolism
  • Signal Transduction
  • Tissue Array Analysis

Substances

  • Interleukin-1
  • Isothiocyanates
  • KRT9 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • Keratin-16
  • Keratin-9
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Keratins
  • sulforaphane