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Harlequin ichthyosis (HI) — the most severe form of keratinizing disorders, often lethal in the neonatal period — is characterized by a profound thickening of the keratin skin layer, a dense “armor”-like scale that covers the body, and contraction abnormalities of the eyes, ears, and mouth. In this issue of the JCI, Akiyama et al. report that mutations in ABCA12 caused defective lipid transport that significantly impacted normal development of the skin barrier. Lipid secretion was recovered after corrective ABCA12 gene transfer into patient keratinocytes. These results should allow for early prenatal diagnosis of HI and lend hope to the possibility of a specific treatment for this devastating disorder.
Waring pointed to what is believed to be the first harlequin fetus described in the US in the diary of Reverend Oliver Hart in 1750 (1). Harlequin ichthyosis (HI) is believed to be inherited in an autosomal-recessive manner, and affected newborn infants are encased in “armor”-like thick, yellow plates of scales with deep red fissuring. The skin is pulled tight such that the face loses its normal appearance and appears frog-like, with eversion of the eyelids (ectropion) and lips (eclabion) and flattening of the ears and nose. The extremities are swollen due to constriction by massive thickening of the skin. Liveborn infants usually die within the first days of life from respiratory, infectious, and/or dehydration-related complications. Some patients treated with retinoids, synthetic derivatives of vitamin A, have survived and subsequently develop severe ichthyosis. The cause of HI, however, has remained elusive, and late prenatal diagnosis has until now relied on electron microscopic examination of tissue sampled by invasive fetal skin biopsy.
Members of the ABCA subclass of the large ABC transporter protein family bind ATP for the active transport of lipids across cell membranes against a concentration gradient. ABCA1 has been shown to be the causative gene in Tangier disease, a disorder of cholesterol transport between liver and other tissues (2–5), while mutations in ABCA4 (expressed exclusively in photoreceptors of the eye for the transport of retinol) cause Stargardt disease, recessive retinitis pigmentosa, or cone-rod dystrophy, in which the abnormal accumulation of retinoids results in the development of macular dystrophy and loss of central vision (6–8).
Lipid processing in the skin is essential for the protective function of the stratum corneum, the most external layer of the epidermis (9). Corneocytes, attached to each other by corneodesmosomes and embedded in intercellular lipid lamellae, form a cornified layer that acts as a barrier between the internal and external environment for bodily defense. The lipid lamellae are derived from lamellar granules, the major lipid-rich organelles present in epidermal granular cells, which originate from the trans-Golgi network. Lamellar granules contain polar lipids (cholesterol sulfate, phospholipids, sphingomyelin, and glucosylceramides) that are the precursors of the intercellular lipids of the stratum corneum. Along with lipids, lamellar granules also transport lipid-processing enzymes and proteases and their inhibitors, all of which play a role in barrier permeability and the control of the desquamation process (10). Lipid-processing enzymes include acid hydrolases, acid sphingomyelinase, β-glucocerebrosidase, and secretory phospholipase A2. At the interface between the granular layer and the first layer of the stratum corneum, lamellar granules normally fuse with the apical cell surface and discharge their lipid contents into the intercellular space; this results in complex changes in lipid composition via the action of these enzymes to form lipid lamellae of the stratum corneum (Figure (Figure1A).1A). The lipid lamellae contain equimolar mixtures of ceramides, cholesterol, and free fatty acids. These structures provide very effective protection against external aggressions and fluid loss.
In a previous study, electron microscopy in HI patients revealed that lamellar granules are either absent or abnormal and that no intercellular lamellae are present (11) (Figure (Figure1B).1B). These data suggest that this defect in the lamellar granules results in thickening of the stratum corneum and the accumulation of armor-like scales in HI. However, the genetic basis for these events had not been elucidated.
Defects in lipid-processing enzymes have previously been shown to cause several other forms of ichthyosis. These include defects in: (a) the steroid sulfatase in X-linked recessive ichthyosis (12); (b) β-glucocerebrosidase in Gaucher disease (13); (c) sphingomyelinase in Niemann-Pick disease (14); (d) fatty aldehyde dehydrogenase in Sjögren-Larsson syndrome (15); (e) lipoxygenase-3 and 12R-lipoxygenase in autosomal-recessive congenital ichthyosis (16); and (f) CGI-58 in Chanarin-Dorfman syndrome (17). Although none of these ichthyoses are as severe as HI, they illustrate that a major role for lipid abnormalities exists in the pathophysiology of ichthyosis.
In this issue of the JCI, Akiyama et al. (18) demonstrate that HI is caused by loss-of-function mutations in ABCA12, which codes for a lamellar granule membrane protein involved in lipid transport (Figure (Figure1A).1A). Together with the knowledge that mutations in ABCA1 and ABCA4 cause Tangier disease and Stargardt disease, respectively, this most recent discovery further supports a pivotal role for ABCA class lipid transporters in cellular homeostasis and sheds light on the importance of lipid processing in the development and maintenance of the epidermal barrier.
The observation of lamellar granule abnormalities in epidermal keratinocytes of HI patients led Akiyama et al. (18) to test the hypothesis that a defect in a major lamellar granule protein could be defective in this disease. The authors drew a parallel between ABCA3, which encodes a lamellar granule membrane protein essential for alveolar surfactant lipid transport and secretion in alveolar lung cells (19), and ABCA12, which harbors missense mutations in autosomal-recessive congenital ichthyosis (20). The authors hypothesized that mutations in ABCA12, more deleterious than those causing autosomal-recessive congenital ichthyosis, may underlie HI — and their hypothesis was correct. They demonstrate that 5 distinct mutations in ABCA12 resulted in truncation or deletion of highly conserved regions of the ABCA12 protein, which disrupts lipid transport (Figure (Figure1B).1B). Interestingly, Kelsell and colleagues very recently used a completely different genomic approach, based on homozygosity mapping using single-nucleotide-polymorphism chip technology, to also identify ABCA12 as the causative gene in HI (21).
As a consequence of impaired ABCA12 function, Akiyama et al. (18) found that lamellar granules were not properly formed and therefore the lipids essential for stratum corneum formation (such as glucosylceramide) were abnormally processed, diffusely distributed, and abnormally secreted or not secreted at all. The lack of lipid lamellae formation in the intercellular space resulted in abnormal barrier formation and extraordinary thickening of the stratum corneum (Figure (Figure11B).
Akiyama et al. (18) also showed that genetic correction of ABCA12 deficiency by gene transfer in patients’ keratinocytes restored normal glucosylceramide cell distribution and lamellar granule formation. This result raises the possibility of HI treatment using systemic administration of functional peptides with ABCA12-like properties or ABCA12 gene delivery approaches undertaken either prior to or after birth.
This discovery of the role of ABCA12 in HI reveals a major role of lipid transport in the formation of the skin barrier and its function. This is a very elegant illustration of adaptive evolution to terrestrial life, involving 2 closely related lipid transporters, ABCA3 and ABCA12, which are essential for the production of alveolar surfactant and lipid lamellae in the stratum corneum, respectively. At birth, while ABCA3 prevents the lungs from collapsing, ABCA12 protects the skin from external aggressions and water loss. Loss of ABCA12 expression results in the most severe dysregulation of cornification in humans, covering the newborn infant in a lethal type of armor. Not only will these findings dramatically improve our ability to offer mutational screening and early DNA-based prenatal diagnosis of HI, but they will also allow for the development of new and specific therapeutic approaches.
See the related article beginning on page 1777.
Nonstandard abbreviations used: HI, harlequin ichthyosis.
Conflict of interest: The author has declared that no conflict of interest exists.