Harlequin Ichthyosis

Harlequin ichthyosis (HI, OMIM #242500) is a severe autosomal recessive congenital skin disorder characterized by thick, armor-like scales covering the body. Symptoms include malformed ears, eyes, and often fused fingers. Major complications at birth include breathing problems and infections. This rare condition, with an incidence of 1 in 300,000 births (survival rate ~56%), is caused by mutations in the ABCA12 gene on the second chromosome. This gene encodes the ABCA12 protein, responsible for transporting lipids essential for proper skin barrier formation. More info

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Pathogenic mechanisms

ABCA12 carries lipids, ceramides, cholesterol and fatty acids to the upper layer of epidermis – stratum corneum, through lamellar bodies. In the case of a mutation in the ABCA12 gene, lipids are not transferred to the lamellar granules, which themselves are abnormally shaped, reduced, or completely absent. As a result, exocytosis of the contents of the lamellar granules is limited, and abnormal lipid-containing vacuoles form corneocytes (terminally differentiated keratinocytes) that would normally peel off in the skin of healthy people. Patients with HI have noticeably thickened skin, because it does not exfoliate, and corneocytes with abnormal lipid vacuoles accumulate in it.

Loss of ABCA12 function leads to impaired lipid transport in keratinocytes, resulting in defective formation of the lipid barrier in the stratum corneum (upper layer of epidermis), defective lamellar granules, and premature differentiation of basal keratinocytes.