Self-improvement of keratinocyte differentiation defects during skin maturation in ABCA12-deficient harlequin ichthyosis model mice

Am J Pathol. 2010 Jul;177(1):106-18. doi: 10.2353/ajpath.2010.091120. Epub 2010 May 20.


Harlequin ichthyosis (HI) is caused by loss-of-function mutations in the keratinocyte lipid transporter ABCA12. The patients often die in the first 1 or 2 weeks of life, although HI survivors' phenotypes improve within several weeks after birth. In order to clarify the mechanisms of phenotypic recovery, we studied grafted skin and keratinocytes from Abca12-disrupted (Abca12(-/-)) mice showing abnormal lipid transport. Abca12(-/-) neonatal epidermis showed significantly reduced total ceramide amounts and aberrant ceramide composition. Immunofluorescence and immunoblotting of Abca12(-/-) neonatal epidermis revealed defective profilaggrin/filaggrin conversion and reduced protein expression of the differentiation-specific molecules, loricrin, kallikrein 5, and transglutaminase 1, although their mRNA expression was up-regulated. In contrast, Abca12(-/-) skin grafts kept in a dry environment exhibited dramatic improvements in all these abnormalities. Increased transepidermal water loss, a parameter representing barrier defect, was remarkably decreased in grafted Abca12(-/-) skin. Ten-passage sub-cultured Abca12(-/-) keratinocytes showed restoration of intact ceramide distribution, differentiation-specific protein expression and profilaggrin/filaggrin conversion, which were defective in primary-cultures. Using cDNA microarray analysis, lipid transporters including four ATP-binding cassette transporters were up-regulated after sub-culture of Abca12(-/-) keratinocytes compared with primary-culture. These results indicate that disrupted keratinocyte differentiation during the fetal development is involved in the pathomechanism of HI and, during maturation, Abca12(-/-) epidermal keratinocytes regain normal differentiation processes. This restoration may account for the skin phenotype improvement observed in HI survivors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Animals
  • Cell Differentiation / physiology*
  • Cells, Cultured
  • Ceramides / metabolism
  • Epidermal Cells*
  • Epidermis / growth & development*
  • Epidermis / pathology
  • Epidermis / transplantation
  • Fetus / anatomy & histology
  • Fetus / physiology
  • Filaggrin Proteins
  • Humans
  • Ichthyosis, Lamellar* / genetics
  • Ichthyosis, Lamellar* / pathology
  • Ichthyosis, Lamellar* / physiopathology
  • Intermediate Filament Proteins / metabolism
  • Keratinocytes / cytology
  • Keratinocytes / physiology*
  • Lipid Metabolism / physiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, SCID
  • Oligonucleotide Array Sequence Analysis


  • ABCA12 protein, human
  • ATP-Binding Cassette Transporters
  • Abca12 protein, mouse
  • Ceramides
  • FLG protein, human
  • Filaggrin Proteins
  • Intermediate Filament Proteins