•The corneocyte lipid envelope is extremely important for the skin barrier.•SDR9C7 catalyzes the dehydrogenation of the lipoxygenase products esterified in CerEOS.•SDR9C7 plays a role in the covalent ...binding of corneocyte lipid envelope to proteins.
Among the components of the barrier structure of the stratum corneum in human skin, the corneocyte lipid envelope (CLE) is extremely important for the skin barrier. The importance of the CLE and esterified ω-hydroxy sphingosine (CerEOS), its main precursor, has been suggested from the fact that mutations in a number of genes involved in CerEOS synthesis and CLE formation have been identified as genetic causes of congenital ichthyoses, which are severe genetic skin disorders. However, the molecule/mechanism involved in the covalent binding of CerEOS to proteins on the outer surface of the cornified cell envelope had been a missing part.
Very recently, we proposed new potential modes of protein binding by covalent reactions of CerEOS-epoxy-enone. We revealed the biochemical function of short-chain dehydrogenase/reductase family 9C member 7 (SDR9C7), encoded by SDR9C7, as catalyzing the dehydrogenation of the lipoxygenase products that are esterified in CerEOS. Epoxy-enone produced by SDR9C7 covalently binds to proteins on the outer extracellular surface of the cornified cell envelope.
Importantly, our recent striking findings were derived from the detailed lipid analysis of only one ARCI patient with SDR9C7 mutation. The combination of detailed analyses of precious samples from a rare patient and the establishment of corresponding animal models is an effective and powerful tool for analyzing rare inherited diseases. This review summarizes this newly revealed mechanism in skin barrier formation, describes the characteristic features of patients with SDR9C7 mutations, and introduces the clinical value of non-invasive analyses for patients with very rare intractable skin diseases.
Inherited ichthyoses are a group of genetic disorders characterized by generalized dry skin, scaling and hyperkeratosis, and often associated with erythroderma. These manifestations are due to ...mutations in genes mostly involved in skin barrier formation. Inherited ichthyoses consist of non‐syndromic ichthyoses and ichthyosis syndromes. Non‐syndromic ichthyoses are characterized by the phenotypic expression of the disorder being seen only in the skin. Non‐syndromic ichthyoses include ichthyosis vulgaris, recessive X‐linked ichthyosis, autosomal recessive congenital ichthyosis, keratinopathic ichthyosis and other forms. This review focuses on updates for each type of non‐syndromic ichthyosis, highlighting molecular mechanisms and phenotype/genotype correlations. Included in autosomal recessive congenital ichthyosis are three of the major phenotypes (harlequin ichthyosis, lamellar ichthyosis and congenital ichthyosiform erythroderma) and three of the minor subtypes (self‐healing collodion baby, acral self‐healing collodion baby and bathing suit ichthyosis). Keratinopathic ichthyosis is proposed as an umbrella term for ichthyoses caused by mutations in keratin genes. Next‐generation sequencing technologies have become powerful tools for the diagnosis of inherited ichthyoses and the discovery of their genetic causes. This article reviews the current understanding of molecular pathomechanisms for non‐syndromic ichthyoses and explores future perspectives.
Generalized pustular psoriasis (GPP) is a chronic, systemic inflammatory disease accompanied by high fever and general malaise. Diffuse erythema and swelling of the extremities occur, with multiple ...sterile pustules all over the body in GPP patients. GPP often relapses over the lifetime and can be life-threatening. Recent discoveries of the underlying molecular genetic basis of many cases of this disorder have provided major advances to clinicians and researchers towards an understanding of the pathomechanism of GPP. However, the therapeutic management of GPP still faces many challenges and much uncertainty, and an evidence-based review summarizing the available clinical data on the management of this heterogeneous disease is needed. The present review addresses challenges regarding the precise clinical diagnosis and evaluation of clinical symptoms in GPP. In addition, we update and briefly summarize the current understanding of molecular pathomechanisms behind GPP as an autoinflammatory keratinization disease. Recent publications have clarified the genetic backgrounds of patients with GPP and ethnic differences in predisposing factors. Although there are ethnic differences in the prevalences of these pathogenic alleles, from recent reports, at most 60.5% (IL36RN), 5.9% (CARD14), and 10.8% (AP1S3) of GPP patients have the mutations/variations of these genes. All the reported biologics studied seemed effective and relatively well tolerated. Although it is difficult to evaluate therapeutic efficacy from studies on just a few cases, recent findings suggest that biologics can be a useful, powerful tool for controlling skin and systemic inflammation in GPP and for improving the quality of life of GPP patients.
•Autoinflammatory keratinization diseases have autoinflammatory pathomechanisms.•The clinical entity “autoinflammatory keratinization diseases” includes IL36Ra-related pustulosis.•CARD14-mediated ...pustular psoriasis falls within the concept of autoinflammatory keratinization diseases.•Pityriasis rubra pilaris type V and keratosis lichenoides chronica are included in autoinflammatory keratinization diseases.•Improved understanding of disease pathophysiology may lead to innovative targeted therapies.
Classifying inflammatory skin diseases is challenging, especially for the expanding group of disorders triggered by genetic factors resulting in hyperactivated innate immunity that result in overlapping patterns of dermal and epidermal inflammation with hyperkeratosis. For such conditions, the umbrella term “autoinflammatory keratinization diseases” (AIKD) has been proposed. AIKD encompasses diseases with mixed pathomechanisms of autoinflammation and autoimmunity, and includes IL-36 receptor antagonist (IL-36Ra)-related pustulosis, CARD14-mediated pustular psoriasis, pityriasis rubra pilaris (PRP) type V, and familial keratosis lichenoides chronica (KLC). Mechanistically, the entities include generalized pustular psoriasis (GPP) without psoriasis vulgaris, impetigo herpetiformis and acrodermatitis continua, which are IL-36Ra-related pustuloses caused by loss-of-function mutations in IL36RN; GPP with psoriasis vulgaris and palmoplantar pustular psoriasis which are CARD14-mediated pustular psoriasiform dermatoses with gain-of-function variants of CARD14; PRP type V which is caused by gain-of-function mutations in CARD14; and, familial KLC in which mutations in NLRP1, an inflammasome sensor protein predominantly expressed in skin, have been identified. It is likely that further inflammatory keratinization disorders will also fall within the concept of AIKD, as elucidation of novel pathogenic mechanisms of inflammatory keratinization diseases emerges. A better understanding of the pathophysiology of AIKD is likely to lead to innovative, targeted therapies that benefit patients.
Keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) syndrome is a rare autosomal recessive skin disorder characterized by palmoplantar keratoderma, linear hyperkeratotic ...plaques, ichthyosiform scaling, circular constrictions around the fingers, and numerous papules distributed linearly in the arm folds and on the wrists. Histologically, the affected skin shows hypertrophy and hyperplasia of the spinous, granular, and horny epidermal layers with mild infiltration of inflammatory cells in the upper dermis. There are 14 patients with KLICK syndrome described in the literature, and they all carry the same nucleotide deletion. Proteasome maturation protein (POMP), encoded by
, is an ubiquitously expressed protein that functions as a chaperone for proteasome maturation. KLICK syndrome is caused by a reduction in POMP levels that leads to proteasome insufficiency in differentiating keratinocytes. It is noteworthy that
is also known to be the causative gene for proteasome-associated autoinflammatory syndrome-2 (PRAAS2). It is considered that the disrupted proteasome assembly caused by the
mutation might lead to both skin inflammation and then hyperkeratosis in KLICK syndrome. Inflammation caused by the hyperactivation of innate immunity occasionally leads to inflammatory diseases of the skin, recently denoted as autoinflammatory keratinization diseases (AiKDs). We propose that KLICK syndrome caused by the specific 1-bp nucleotide deletion mutation in the regulatory region of
might be in a spectrum of proteasome-associated phenotypes.
Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the ...inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasome disorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 to skin inflammatory syndromes and skin cancer predisposition.
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•Germline, gain-of-function NLRP1 mutations cause MSPC and FKLC syndromes.•Mutant NLRP1 proteins have lower threshold for inflammasome activation.•The Pyrin (PYD) and LRR domains of NLRP1 inhibit its self-oligomerization.•NLRP1 mutants cause skin hyperplasia via paracrine inflammatory signaling.
Gain-of-function mutations in the inflammasome sensor NLRP1 increase susceptibility to skin cancer and unmask unique regulatory autoinhibition in the inflammasome.
A 55-year-old Japanese man was diagnosed with VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, which is a newly documented adult-onset autoinflammatory disease caused by ...somatic UBA1 mutations 1, after four years of symptoms. He had suffered from recurrent fever after the onset of systemic arthralgia, scleritis, periorbital/orbital inflammation, optic perineuritis (A, B, T1-weighted contrast-enhanced magnetic resonance imaging in C and D, arrow in D), and myelodysplastic syndrome.
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