Abstract
Harlequin Ichthyosis is a severe skin disease caused by mutations in the human gene encoding ABCA12. Here, we characterize a novel mutation in intron 29 of the mouse Abca12 gene that leads to the loss of a 5’ splice donor site and truncation of the Abca12 RNA transcript. Homozygous mutants of this smooth skin or smsk allele die perinatally with shiny translucent skin, typical of animal models of Harlequin Ichthyosis. Characterization of smsk mutant skin showed that the delivery of glucosylceramides and CORNEODESMOSIN was defective, while ultrastructural analysis revealed abnormal lamellar bodies and the absence of lipid lamellae in smsk epidermis. Unexpectedly, mutant stratum corneum remained intact when subjected to harsh chemical dissociation procedures. Moreover, both KALLIKREIN 5 and -7 were drastically decreased, with retention of desmoplakin in mutant SC. In cultured wild type keratinocytes, both KALLIKREIN 5 and -7 colocalized with ceramide metabolites following calcium-induced differentiation. Reducing the intracellular levels of glucosylceramide with a glucosylceramide synthase inhibitor resulted in decreased secretion of KALLIKREIN proteases by wild type keratinocytes, but not by smsk mutant keratinocytes. Together, these findings suggest an essential role for ABCA12 in transferring not only lipids, which are required for the formation of multilamellar structures in the stratum corneum, but also proteolytic enzymes that are required for normal desquamation. Smsk mutant mice recapitulate many of the pathological features of HI and can be used to explore novel topical therapies against a potentially lethal and debilitating neonatal disease.
Highlights
Harlequin Ichthyosis (HI, OMIM 242500) is one of the most severe recessive congenital skin diseases [1,2,3]
We have identified a novel mutation in Abca12 that elicits many of the features of HI, including severe hyperkeratosis, lamellar bodies (LBs) defects, absence of intercellular lipid lamellae, aberrant protein processing, defective lipid trafficking, limb contractures and the absence of skin barrier function
We present several lines of evidence indicating that the hyperkeratosis observed in HI is likely caused by a severe defect in desquamation
Summary
Harlequin Ichthyosis (HI, OMIM 242500) is one of the most severe recessive congenital skin diseases [1,2,3]. Armor-like skin plates separated by deep fissures. These skin plates are hard and thick, they are ineffective as a permeability barrier [4]. The hard skin plates constrict body movements, and cause the malformation of ears, eyelids and lips during development [5]. The barrier defects and the deep fissures lead to excessive water and heat loss, and render HI patients more susceptible to environmental insults [6]. Even with improvements during intensive perinatal care, many HI infants die soon after birth [7, 8]
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