Comprehensive stratum corneum ceramide profiling reveals reduced acylceramides in ichthyosis patient with CERS3 mutations

Abstract

The stratum corneum (SC) of the epidermis acts as a skin permeability barrier, and abnormalities in SC formation lead to several skin disorders. Lipids, especially the epidermisspecific ceramide classes ω-O-acylceramides (acylceramides) and protein-bound ceramides, are essential for skin barrier formation. Ceramide synthase 3 (CERS3) is involved in the synthesis of acylceramides and protein-bound ceramides, and CERS3 mutations cause autosomal recessive congenital ichthyosis. In the present study, we measured ceramide synthase activity and performed comprehensive SC ceramide profiling in an ichthyosis patient with compound heterozygous CERS3 mutations: nonsense mutation p.Arg75* and missense mutation p.Arg229His. The activity of p.Arg75* and p.Arg229His mutant CERS3 proteins was reduced to 4% and 56%, respectively, of the wild-type protein. In the patient's SC, acylceramide levels were greatly reduced, but the levels of protein-bound ceramides remained almost unchanged. Non-acylated ceramide levels were also affected in the patient; in particular, the levels of ceramides composed of sphingosine and non-hydroxy or α-hydroxy fatty acid were substantially higher than in healthy controls. These results suggest that a reduction in acylceramide levels alone leads to ichthyosis. Although protein-bound ceramides are synthesized from acylceramides, levels of acylceramides and protein-bound ceramides are not necessarily correlated.

Natural Ingredients of Transdermal Drug Delivery Systems as Permeation Enhancers of Active Substances through the Stratum Corneum

“…Current scientific research does not directly describe topically applied ceramides as penetration enhancers for APIs, but their role in modulating the barrier properties of the epidermis has been confirmed. Studies have evaluated the influence of the fatty chain and the size of the polar head of ceramides on the permeability of externally applied substances, which suggests the potential for ceramides as future penetration enhancers for APIs. ,− In healthy human SC, ceramides contain fatty acid residue chains of more than 22 carbon atoms (Table , item 3). ,, Shorter ceramide chains are observed in dermatoses that damage the skin barrier, such as atopic dermatitis, lamellar ichthyosis, Netherton syndrome, psoriasis, and autosomal recessive congenital ichthyosis. ,− The effect of ceramide acyl chain length on SC barrier integrity has been confirmed in studies, − in which it was observed that replacing the acyl chain in nonhydroxy acyl sphingosine-type ceramides (CER NS) of C24 length with a shorter one (C4–6) resulted in a significantly increased SC lipid permeability. An in vitro permeability study by Školova et al using Franz diffusion cells of 5% theophylline (180 g/mol, LogP = 0) and 2% indomethacin (358 g/mol, LogP = 4.3) showed that replacement of CER NS (C24) with CER NS (C6) resulted in an increase of approximately 3.5 times the permeation of theophylline and nearly 6.5 times that of indomethacin.…”

“…Studies have evaluated the influence of the fatty chain and the size of the polar head of ceramides on the permeability of externally applied substances, which suggests the potential for ceramides as future penetration enhancers for APIs. 113 , 134 − 136 In healthy human SC, ceramides contain fatty acid residue chains of more than 22 carbon atoms ( Table 2 , item 3). 108 , 137 , 138 Shorter ceramide chains are observed in dermatoses that damage the skin barrier, such as atopic dermatitis, lamellar ichthyosis, Netherton syndrome, psoriasis, and autosomal recessive congenital ichthyosis.…”

Current insights into skin lipids and their roles in cutaneous health and disease

“…Conversely, inflammatory skin conditions characterized by barrier abnormalities clearly show differences in the stratum corneum lipidome. Mutations in PNPLA1 alter the formation of acylceramides in ichthyosis [20 ▪ ], while the increased prevalence of short-chain ceramides observed in atopic dermatitis, psoriasis and ichthyosis modifies the stratum corneum lipid organization, and correlates with barrier dysfunction, a conclusion confirmed using model membrane systems [21,22,23 ▪▪ ,24].…”

Congenital Ichthyosis: Clinical and Genetic Characteristics of the Disease

“…Вместе с тем отмечено наличие пятнистой эритемы при патогенном варианте в гене NIPAL4, выпадение волос, стойкий эклабиум -при изменениях в гене ABCA12, артрит или ограничения подвижности суставов -в генах TGM1, ABCA12, NIPAL4, онихолизисв гене SDR9C7, мономорфные коричневые пластиныв гене CYP4F22 [24]. В других исследованиях показали, что больные с двуаллельными патогенными вариантами гена CERS3 всегда имели коллодиевую мембрану при рождении, эритему и мелкие чешуйки на лице и туловище, более крупные коричневые плоские ромбовидные чешуйки с легкой эритемой на нижних конечностях, а также ладонно-подошвенную гиперлинейность, гиперкератоз [33,39] не описаны [1]. Изменения в гене ALOX12B более чем в 60% случаев ассоциируют с фенотипами PI -SICI, AсSHCB, BSI [13,42].…”

“…Участвует в синтезе липидов и в их метаболизме во время формирования эпидермального барьера плода, в процессах кератинизации и терминальной дифференцировки кератиноцитов. Дефект в гене приводит к нарушению указанных молекулярных процессов[31,32] LIPNЛипаза N LI, CIE Нарушение дифференцировки кератиноцитовCERS3Керамид-синтетаза 3 CERS3 LI, CIE Нарушение синтеза ацилцерамидов и связанных с белками церамидов, особенно с длинноцепочечными фрагментами[33]…”