Mutations in lipid transporter ABCA12 cause HI. (A) In the granular layers of healthy skin, the ABCA12 lipid transporter transfers lipids from the cytosol into lamellar granules where lipid-processing enzymes, proteases, and protease inhibitors are also concentrated. At the granular layer–stratum corneum interface, the lamellar granules fuse with the cell membrane and discharge their content into the intercellular lamellae. Complex enzymatic reactions lead to modifications of the lipid composition of the intercellular space (cholesterol, ceramides, free fatty acids) that provide a very effective water-permeability barrier. Corneocytes detach from each other in the superficial layers of the stratum corneum as a result of finely regulated proteolytic cleavage of corneodesmosomes. (B) In the skin of HI patients, the absence of ABCA12 prevents the transfer of lipids into lamellar granules, which themselves are abnormally shaped, reduced in number, or absent. As a result, exocytosis of lamellar granule content is reduced and intercellular lipid lamellae are absent. Abnormal lipid-containing vacuoles form in the cytoplasm of the corneocytes. The stratum corneum is remarkably thickened and does not desquame.