Basis For Abnormal Desquamation And Permeability Barrier Dysfunction in RXLI

Abstract

Mutations in the gene for steroid sulfatase (SSase), are responsible for recessive x-linked ichthyosis (RXLI). As a consequence of SSase deficiency, its substrate, cholesterol sulfate (CSO4), accumulates in the epidermis. Accumulation of this amphipathic lipid in the outer epidermis provokes both a typical scaling phenotype and permeability barrier dysfunction. Research on RXLI has illuminated several, potentially overlapping pathogenic mechanisms and provided insights about the role of SSase and CSO4 in normal differentiation, barrier maintenance, and desquamation. We now show here that SSase is concentrated in lamellar bodies (LB), and secreted into the SC interstices, along with other LB-derived lipid hydrolases. There, it degrades CSO4, generating some cholesterol for the barrier, while the progressive decline in CSO4 (a serine protease (SP) inhibitor) permits corneodesmosome (CD) degradation leading to normal desquamation. Two molecular pathways contribute to disease pathogenesis in RXLI: 1) excess CSO4 produces nonlamellar phase separation in the stratum corneum (SC) interstices, explaining the barrier abnormality. 2) The increased CSO4 in the SC interstices inhibit activity sufficiently to delay CD degradation, leading to corneocyte retention. We also show here that increased Ca++ in the SC interstices in RXLI could contribute to corneocyte retention, by increasing CD and interlamellar cohesion. RXLI represents one of the best understood diseases in dermatology--from the gene to the SC interstices, its etiology and pathogenesis are becoming clear, and assessment of disease mechanisms in RXLI led to new insights about the role of SSase and CSO4 in epidermis terminal differentiation.

Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009

“…157,158 In recent years, it has become evident that this most critical SC functionethe permeability barriereis impaired in most ichthyosis forms. 11,60,[159][160][161][162][163][164] Several murine knockout models for ichthyosis [Spink5 (e/e), Tgm1 (e/e), Abca12 (e/e) mice, [165][166][167] Alox12b (e/e), 168 Cldn1(e/e) 169 ] have demonstrated neonatal lethality as a result of dehydration, underscoring the critical role of these genes in permeability barrier competence. Mutations that either alter the lipid composition of the SC membranesedisorders of lipid metabolismeor affect the function of the corneocyte structural proteinsedisorders of keratinocyte proteinseresult in increased water movement through the intercellular pathway.…”

“…7 The combination of all alterations observed with this technique may be diagnostic for many forms of ichthyosis. 8 Most importantly, the ultrastructural demonstration of disturbances of lipid metabolism gives valuable insights into the pathophysiologic basis of many ichthyoses 11,60,[159][160][161][162][163][164] and enables a function-driven approach. 7,8,11 Histopathology, immunochemistry, and other nongenetic analyses Routine histopathological findings in most ichthyoses are nondiagnostic, often demonstrating only epidermal hyperplasia and varying degrees of orthohyperkeratosis.…”

Inherited ichthyoses/generalized Mendelian disorders of cornification

“…39,52 XLI (STS) typically shows retained corneodesmosomes and phase separation of lipids in the stratum corneum interstices. 53 Harlequin ichthyosis (ABCA12) and CEDNIK (SNAP29) exhibit abnormal LBs 54 due to impaired lipid transport and abnormal intercellular lamellae in the stratum corneum. 55 Gaucher disease (glucocerebrosidase (GBA)) is characterized by impaired processing of the extracellular lipids derived from the LBs.…”

Thematic Review Series: Skin Lipids. Peroxisome proliferator-activated receptors and liver X receptors in epidermal biology

“…Cholesterol sulfotransferase type 2B isoform 1b (SULT2B1b) is a key enzyme in the synthesis of cholesterol sulfate, a critical regulator of keratinocyte differentiation and desquamation, as well as a mediator of barrier homeostasis (84,85). PPAR and LXR activators increased SULT2B1b mRNA levels in keratinocytes independently of their differentiation stage, with the most dramatic effect (a 26-fold increase) induced by the PPARg activator ciglitazone (86).…”