Thick Skinned: ABCA12 Gene and its Role in Harlequin Ichthyosis Lacy Huffman & J. B. Phillips, Ph.D. Cumberland University Introduction Harlequin Ichthyosis Regulation Ø The ABCA12 gene is responsible for making the ATP- Ø Known as the worst ichthyosis disorder, it is an binding cassette transporter proteins that transport Ø The ABCA12 protein transports lipid glucosylceramides autosomal recessive disorder in which the keratin layer molecules across cell membranes. (GlcCer) through lamellar granules (LGs) to the of the skin is thicker and forms large plates and cracks extracellular space.3 on the body.2 Ø Specifically, the ABCA12 protein is necessary for normal skin development. Ø In the extracellular space, glucosylceramides are Ø Characterized by dehydrated skin and an increased hydrolyzed into hydroxyceramides.3 chance of infection due to ineffective skin barrier. Ø Mutations in this gene can lead to harlequin ichthyosis, Ø These ceramides comprise part of the lipid envelope, Ø In previous years, infants would not survive that long, but a skin condition present at lamellar membrane, and lamellar granules.3 survival has increased with the development of neonatal birth that makes the skin care (Fig 3). hard and thick. Ø The lipid envelope, lamellar envelope, and lamellar granules in the epidermis function to form the skin barrier, Ø Care includes incubation with high humidity, lubrication Ø This gene is found on keeping the skin hydrated and protected.3 on the eyes, nutrition supplements, use of retinoids and chromosome 2q34 (Fig 1). Figure 1: Location on chromosome5 antibiotics, and monitoring of body weight and fluids.1 Gene can be found on the long arm Ø Opposed to the normal function of the ABCA12 gene, (q) of chromosome 2 on band 34. mutations in this process lead to skin disorders (Fig 2). History Ø Scientists at the Centre for Cutaneous Research in London compared DNA sequences of affected and Figure 3: Harlequin ichthyosis improvement 1 unaffected children with harlequin ichthyosis and targeted it to the gene ABCA12.4 A newborn suffering from harlequin ichthyosis on the left, and the same newborn 4 months later after receiving neonatal care and 0.5 mg/kg dose Ø Japanese scientists also identified mutations in of acitretin per day.1 ABCA12, which were thought to shorten or delete some regions in the protein.4 Ø The Japanese scientists then tested how the ABCA12 References protein affected lamellar granules and parts of the 1. Glick, Jaimie B, et al. “Improved Management of Harlequin Ichthyosis With Advances in lamellar granule-cell membrane fusion in normal cells Neonatal Intensive Care.” Pediatrics, vol. 139, no. 1, 2016, doi:10.1542/peds.2016- of the epidermis.4 1003. 2. Lai, Yurong. “Membrane Transporters and the Diseases Corresponding to Functional Ø These scientists observed how ABCA12 was Defects.” Transporters in Drug Discovery and Development, 2013, pp. 1–146., doi:10.1533/9781908818287.1. expressed in the normal keratinization of the 3. Scott, Claire A., et al. “Harlequin Ichthyosis: ABCA12 Mutations Underlie Defective Lipid epidermis.4 Figure 2: Normal ABCA12 gene function vs loss of gene function 3 Transport, Reduced Protease Regulation and Skin-Barrier Dysfunction.” Cell and Tissue Research, vol. 351, no. 2, 2012, pp. 281–288., doi:10.1007/s00441-012-1474-9. Ø Ultimately, it was confirmed that the mutations caused This shows the regulation process of the ABCA12 gene in skin 4. Uitto, Jouni. Gene for Harlequin Ichthyosis Found: Foundation for Ichthyosis (FIRST). congestion of lipid secretion in the skin of those who development and the mutated process leading to skin disorders. www.firstskinfoundation.org/gene-for-harlequin-ichthyosis-found-2005. have harlequin ichthyosis disorder.4 5. http://ribosome.med.miyazaki-u.ac.jp/RPDB/Map/RPL37A.gif.