SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin barrier formation

Takeichi, Takuya; Hirabayashi, Tetsuya; Miyasaka, Yuki; Kawamoto, Akane; Okuno, Yusuke; Taguchi, Shuichi; Tanahashi, Kana; Murase, Chiaki; Takama, Hiroyuki; Tanaka, Kenichi; We, Boeglin; Mw, Calcutt; Watanabe, Daisuke; Kono, Michihiro; Muro, Yoshinao; Ishikawa, Junko; Ohno, Tamio; Ar, Brash; Akiyama, Masashi

doi:10.1172/jci130675

Cited by 63 publications

(97 citation statements)

References 55 publications

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“…ALOXE3 deficiency is associated with impaired ceramide processing which may lead to accumulation of ceramides precursors. [31,32] These may be used as substrates for epidermal ceramidases and as a result may cause increase in epidermal free fatty acid content and decrease in stratum corneum pH. [33] As increase in stratum corneum pH was shown to F I G U R E 3 Corneodesmosin protein expression in keratinocytes downregulated for ALOXE3.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic suppression of acral peeling skin syndrome in a patient with autosomal recessive congenital ichthyosis

Mohamad

Nanda²,

Pavlovsky

et al. 2020

Experimental Dermatology

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Autosomal recessive congenital ichthyosis (ARCI) manifests with generalized scaling often associated with generalized erythema. Mutations in at least 13 different genes have been reported to cause ARCI. Acral peeling skin syndrome (APSS) is a rare autosomal recessive disorder manifesting with peeling over the distal limbs and dorsal surfaces of hands and feet. APSS is mostly due to mutations in TGM5, encoding transglutaminase 5. Both ARCI and APSS are fully penetrant genetic traits. Here, we describe a consanguineous family in which one patient with mild ARCI was found to carry a homozygous mutation in ALOXE3 (c.1238G > A; p.Gly413Asp). The patient was also found to carry a known pathogenic homozygous mutation in TGM5 (c.1335G > C; p.Lys445Asn) but did not display acral peeling skin. Her uncle carried the same homozygous mutation in TGM5 but carried the ALOXE3 mutation in a heterozygous state and showed clinical features typical of APSS. Taken collectively, these observations suggested that the ALOXE3 mutation suppresses the clinical expression of the TGM5 variant. We hypothesized that ALOXE3 deficiency may affect the expression of a protein capable of compensating for the lack of TGM5 expression. Downregulation of ALOXE3 in primary human keratinocytes resulted in increased levels of corneodesmosin, which plays a critical role in the maintenance of cell‐cell adhesion in the upper epidermal layers. Accordingly, ectopic corneodesmosin expression rescued the cell‐cell adhesion defect caused by TGM5 deficiency in keratinocytes as ascertained by the dispase dissociation assay. The present data thus provide evidence for phenotypic suppression in a human hereditary skin disorder.

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Section: Discussionmentioning

confidence: 99%

Phenotypic suppression of acral peeling skin syndrome in a patient with autosomal recessive congenital ichthyosis

Mohamad

Nanda²,

Pavlovsky

et al. 2020

Experimental Dermatology

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“…Mutations in SDR9C7, encoding a short-chain dehydrogenase/reductase family 9C member 7 (SDR9C7), have been recently found in ichthyosis. Complete loss of a species of ω-О-acylceramide esterified with linoleate-9,10-trans-epoxy-11E-13-ketone has been proposed as the mechanism based on the result from a knockout Sdr9c7 mouse [87]. Long-term use of topical glucocorticoids could alter the SC lipid profiles, particularly long-chain ester-linked ceramide, thereby leading to skin barrier defects [88].…”

Section: Skin Lipidsmentioning

confidence: 99%

Molecular Mechanism of Epidermal Barrier Dysfunction as Primary Abnormalities

Lee

2020

IJMS

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Epidermal barrier integrity could be influenced by various factors involved in epidermal cell differentiation and proliferation, cell-cell adhesion, and skin lipids. Dysfunction of this barrier can cause skin disorders, including eczema. Inversely, eczema can also damage the epidermal barrier. These interactions through vicious cycles make the mechanism complicated in connection with other mechanisms, particularly immunologic responses. In this article, the molecular mechanisms concerning epidermal barrier abnormalities are reviewed in terms of the following categories: epidermal calcium gradients, filaggrin, cornified envelopes, desquamation, and skin lipids. Mechanisms linked to ichthyoses, atopic dermatitis without exacerbation or lesion, and early time of experimental irritation were included. On the other hand, the mechanism associated with epidermal barrier abnormalities resulting from preceding skin disorders was excluded. The molecular mechanism involved in epidermal barrier dysfunction has been mostly episodic. Some mechanisms have been identified in cultured cells or animal models. Nonetheless, research into the relationship between the causative molecules has been gradually increasing. Further evidence-based systematic data of target molecules and their interactions would probably be helpful for a better understanding of the molecular mechanism underlying the dysfunction of the epidermal barrier.may not be the primary events in lesional skin. However, they can play a role in part as primary abnormalities because abnormalities in the epidermal barrier are already present in non-lesional skin of atopic dermatitis [1]. Epidermal trauma from tape stripping or irritant application also leads to initial disruption of the barrier, although the result at certain time points may be combined with compensatory reactions followed by trauma.Causative mechanisms involved in primary epidermal barrier dysfunction might be more valuable for the prevention of skin diseases induced by barrier abnormalities. However, the underlying mechanism has been discussed mainly in connection with immunologic responses, including cytokine production [1,9,10]. Accordingly, this review covers molecular mechanisms of epidermal barrier dysfunction as primary abnormalities by focusing on the causative factors of skin diseases (atopic dermatitis and ichthyoses) and experimental skin conditions (tape stripping and irritant application) associated with skin barrier abnormalities. Molecular Mechanisms Related to Epidermal Barrier DysfunctionFormation and maintenance of skin barrier integrity could be influenced by genetic and environmental factors involved in epidermal cell differentiation and proliferation, cell-cell adhesion, and skin lipids. Mechanisms related to epidermal barrier dysfunction at molecular levels have commonly illustrated filaggrin mutations [3,11]. Regarding the mechanism behind skin barrier integrity, the role of epidermal calcium gradients could be considered based on their influence on keratinocyte proliferation and dif...

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“…Using more sophisticated detection methods, such as ultra-performance liquid chromatography and massspectrum detection, the skin levels of fatty acids of different chain lengths, squalene and various types of ceramides (Cer) are quantifiable with high sensitivity and specificity (65)(66)(67). Indeed, the abnormal levels of various ceramides found in ARCI epidermis gave early clues to the existence of inborn errors of acylCer biosynthesis (68), which was later confirmed via gene hunting.…”

Section: Biochemical and Genetic Studies Of Epidermismentioning

confidence: 99%

Ichthyosis: A Road Model for Skin Research

Vahlquist¹,

Törmä²

2020

Acta Derm Venerol

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Ichthyosis refers to skin diseases with scaling somewhat reminiscent of fish scales (Greek: ichthus=fish). There are more than 50 genetic types of, mostly non-syndromic, ichthyosis, ranging in severity and frequency from mild and common (prevalence < 1%) to severe and rare (< 0.001%). In the latter case, babies are often born with a thick horny layer (collodion), dermal inflammation and impaired skin barrier function, requiring intensive medical care. Nearly all patients with ichthyosis require daily applications of cream, sometimes complemented with retinoid tablets. This review highlights recent progress in the understanding of the causes and consequences of ichthyosis, which may lead to better care and treatments. The understanding of monogenetic disorders of cornification, including the group of diseases called ichthyoses, has expanded greatly in recent years. Studies of the aetiology of more than 50 types of ichthyosis have almost invariably uncovered errors in the biosynthesis of epidermal lipids or structural proteins essential for normal skin barrier function. The barrier abnormality per se may elicit epidermal inflammation, hyperproliferation and hyperkeratosis, potentially contributing to the patient's skin symptoms. Despite this and other new knowledge about pathomechanisms, treatment of ichthyosis often remains unsatisfactory. This review highlights a series of approaches used to elucidate the pathobiology and clinical consequences of different types of ichthyosis, and related diseases with the ultimate goal of finding new and better treatments.

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SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin barrier formation

Cited by 63 publications

References 55 publications

Phenotypic suppression of acral peeling skin syndrome in a patient with autosomal recessive congenital ichthyosis

Phenotypic suppression of acral peeling skin syndrome in a patient with autosomal recessive congenital ichthyosis

Molecular Mechanism of Epidermal Barrier Dysfunction as Primary Abnormalities

Ichthyosis: A Road Model for Skin Research

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