Human Molecular Genetics Advance Access originally published online on July 15, 2008
Human Molecular Genetics 2008 17(19):3075-3083; doi:10.1093/hmg/ddn204
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Harlequin ichthyosis model mouse reveals alveolar collapse and severe fetal skin barrier defects
1 Department of Dermatology 2 Department of Molecular and Cellular Pathology, Hokkaido University Graduate School of Medicine, N15W7, Kita-ku, Sapporo 060-8638, Japan
* To whom correspondence should be addressed. Tel: +81 117161161; Fax: +81 117067820; Email: shimizu{at}med.hokudai.ac.jp
Received June 5, 2008; Accepted July 11, 2008
Harlequin ichthyosis (HI), which is the most severe genodermatosis, is caused by loss-of-function mutations in ABCA12, a member of the ATP-binding cassette transporter family. To investigate the pathomechanism of HI and the function of the ABCA12 protein, we generated ABCA12-deficient mice (Abca12–/–) by targeting Abca12. Abca12–/– mice closely reproduce the human HI phenotype, showing marked hyperkeratosis with eclabium and skin fissure. Lamellar granule abnormalities and defective ceramide distribution were remarkable in the epidermis. Skin permeability assay of Abca12–/– fetuses revealed severe skin barrier dysfunction after the initiation of keratinization. Surprisingly, the Abca12–/– mice also demonstrated lung alveolar collapse immediately after birth. Lamellar bodies in alveolar type II cells of the Abca12–/– mice lacked normal lamellar structures. The level of surfactant protein B, an essential component of alveolar surfactant, was reduced in the Abca12–/– mice. Fetal therapeutic trials with systemic administration of retinoid or dexamethasone, which are effective for HI and respiratory distress, respectively, to the pregnant mother mice neither improved the skin phenotype nor extended the survival period. Our HI model mice reproduce the human HI skin phenotype soon after the initiation of fetal skin keratinization and provide evidence that ABCA12 plays pivotal roles in lung and skin barrier functions.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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