How one Protein Can Kill: An Examination of Harlequin Ichthyosis

How One Protein Can Kill:

An Examination of Harlequin Ichthyosis

An infant born with harlequin ichthyosis (HI) is phenotypically distinguished by a covering of thick scales with deep, red fissuring. Most neonates with this congenital defect are born prematurely and rarely survive beyond their first days outside the womb (Hovnanian 2007). Recent research has determined that the condition is due to a mutation of the gene that encodes for ABCA12 protein. This protein functions in the transportation of lipids to the intercellular layer of the stratum corneum, which is the external layer of the epidermis. This mutation causes the loss or non-functionality of ABCA12 protein and results in the inability to hold the outer layer of epidermal skin cells together (Akiyama et al. 2007).

The stratum corneum is responsible for providing protection against external threats and is also important in regulating fluid loss by holding the keratinized skin cells tightly together. Imagine, for example, how fragile a brick wall (cells) would be if it were not held together with mortar (lipids). Normally, the lipids are deposited into the stratum corneum via the lamellar granules (LGs). LGs originate from the Golgi apparatus and are the most common secretory organelles found in the cytoplasm of epidermal cells, making their loss or improper function highly detrimental. Therefore, when functional ABCA12 protein is absent from the cells, the cytoplasm in the stratum corneum becomes thick and congested with dense lipid-containing vacuoles and no normal LGs, giving rise to the phenotypes seen in harlequin infants (Akiyama et al. 2007).

The ABCA12 protein is a member of a large family of ATP-binding Cassette (ABC) transporters. These proteins, through active transport, transfer biomolecules such as lipids across cell membranes (Akiyama 2007). Specifically, ABCA12 is responsible for transferring lipids to the LGs, which then attach to the apical cell surface and release their lipid and protease components into the intercellular layer, forming the skin’s hydrophobic sphingolipid seal. Since the ABCA12 protein is either absent or non-functional in HI, there is little lipid transport in keratinized cells, thus there is only an extremely weak intercellular layer holding the stratum corneum together (Au 2007).

In the last several years, research has pinpointed the ABCA12 mutation to chromosome 2 in region 35. The 2,595 amino acids and 53 coding exons that comprise the ABCA12 protein have been identified. Genetic studies have determined that harlequin ichthyosis is predominantly caused by homozygous mutations, indicating that an autosomal-recessive inheritance is responsible. Furthermore, therapeutic gene transfer studies have also proven that lipid transport in the epidermis has been restored when the wild-type ABCA12 gene is injected into cultured keratinocytes, the main epidural cell, of patients with the disease (Au 2007).

This success of