Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 283, Issue 52, Pages 36624-36635Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M807377200
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Funding
- National Institutes of Health [RR020345, HL074136]
- Inflammatory Bowel Disease [DK43351]
- Boston Area Diabetes and Endocrinology Research Center Award [DK57521]
- National Science Foundation (NSF) [MCB0455318, 0521587]
- NSF EPSCoR [EPS-0236913]
- State of Kansas through Kansas Technology Enterprise Corporation
- Kansas State University
- NIH [P20 RR16475]
- National Center for Research Resources
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [0920663] Funding Source: National Science Foundation
- Div Of Biological Infrastructure
- Direct For Biological Sciences [0521587] Funding Source: National Science Foundation
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Harlequin ichthyosis is a congenital scaling syndrome of the skin in which affected infants have epidermal hyperkeratosis and a defective permeability barrier. Mutations in the gene encoding a member of the ABCA transporter family, ABCA12, have been linked to harlequin ichthyosis, but the molecular function of the protein is unknown. To investigate the activity of ABCA12, we generated Abca12 null mice and analyzed the impact on skin function and lipid content. Abca12(-/-) mice are born with a thickened epidermis and die shortly after birth, as water rapidly evaporates from their skin. In vivo skin proliferation measurements suggest a lack of desquamation of the skin cells, rather than enhanced proliferation of basal layer keratinocytes, accounts for the 5-fold thickening of the Abca12(-/-) stratum corneum. Electron microscopy revealed a loss of the lamellar permeability barrier in Abca12(-/-) skin. This was associated with a profound reduction in skin linoleic esters of long-chain omega-hydroxyceramides and a corresponding increase in their glucosyl ceramide precursors. Because omega-hydroxyceramides are required for the barrier function of the skin, these results establish that ABCA12 activity is required for the generation of long-chain ceramide esters that are essential for the development of normal skin structure and function.
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