Harlequin ichthyosis: ABCA12 mutations underlie defective lipid transport, reduced protease regulation and skin-barrier dysfunction.

[lamellar ichthyosis]

Harlequin ichthyosis (HI ) is a devastating autosomal recessive congenital skin disease . It has been vital to elucidate the biological importance of the protein ABCA 12 in skin -barrier permeability , following the discovery that ABCA 12 gene mutations can result in this rare disease . ATP-binding cassette transporter A 12 (ABCA 12 ) is a member of the subfamily of ATP-binding cassette transporters and functions to transport lipid glucosylceramides (GlcCer ) to the extracellular space through lamellar granules (LGs ). GlcCer are hydrolysed into hydroxyceramides extracellularly and constitute a portion of the extracellular lamellar membrane , lipid envelope and lamellar granules . In HI skin , loss of function of ABCA 12 due to null mutations results in impaired lipid lamellar membrane formation in the cornified layer , leading to defective permeability of the skin barrier . In addition , abnormal lamellar granule formation (distorted shape , reduced in number or absent ) could further cause aberrant production of LG -associated desquamation enzymes , which are likely to contribute to the impaired skin barrier in HI . This article reviews current opinions on the patho-mechanisms of ABCA 12 action in HI and potential therapeutic interventions based on targeted molecular therapy and gene therapy strategies .