Tofacitinib reduces skin inflammation in a patient with severe autosomal recessive congenital ichthyosis
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE228449 | GEO | 2023/04/03
REPOSITORIES: GEO
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Project description:The stratum corneum of the epidermis acts as a life-sustaining permeability barrier. Unique heterogeneous ceramides, especially ω-O-acylceramides, are key components for the formation of stable lamellar membrane structures in the stratum corneum and are essential for a vital epidermal permeability barrier. Several enzymes involved in acylceramide synthesis have been demonstrated to be associated with ichthyosis. The function of patatin-like phospholipase domain-containing protein 1 (PNPLA1) was a mystery until the finding that PNPLA1 gene mutations were involved in autosomal-recessive congenital ichthyosis (ARCI) patients, both humans and dogs. PNPLA1 plays an essential role in the biosynthesis of acylceramide as a CoA-independent transacylase. PNPLA1 gene mutations cause decreased acylceramide levels and impaired skin barrier function. More and more mutations in PNPLA1 genes have been identified in recent years. Herein, we describe the structural and functional specificity of PNPLA1, highlight its critical roles in acylceramide synthesis and skin barrier maintenance, and summarize the PNPLA1 mutations currently identified in ARCI patients.
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Project description:Autosomal recessive congenital ichthyosis (ARCI) is a rare genetic disorder of the skin characterized by abnormal desquamation over the whole body. In this study we report four patients from three consanguineous Tunisian families with skin, eye, heart, and skeletal anomalies, who harbor a homozygous contiguous gene deletion syndrome on chromosome 15q26.3. Genome-wide SNP-genotyping revealed a homozygous region in all affected individuals, including the same microdeletion that partially affects two coding genes (ADAMTS17, CERS3) and abolishes a sequence for a long non-coding RNA (FLJ42289). Whereas mutations in ADAMTS17 have recently been identified in autosomal recessive Weill-Marchesani-like syndrome in humans and dogs presenting with ophthalmologic, cardiac, and skeletal abnormalities, no disease associations have been described for CERS3 (ceramide synthase 3) and FLJ42289 so far. However, analysis of additional patients with non-syndromic ARCI revealed a splice site mutation in CERS3 indicating that a defect in ceramide synthesis is causative for the present skin phenotype of our patients. Functional analysis of patient skin and in vitro differentiated keratinocytes demonstrated that mutations in CERS3 lead to a disturbed sphingolipid profile with reduced levels of epidermis-specific very long-chain ceramides that interferes with epidermal differentiation. Taken together, these data present a novel pathway involved in ARCI development and, moreover, provide the first evidence that CERS3 plays an essential role in human sphingolipid metabolism for the maintenance of epidermal lipid homeostasis.
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Project description:Ichthyoses are a clinically and genetically heterogeneous group of genodermatoses associated with abnormal scaling of the skin over the whole body. Mutations in nine genes are known to cause non-syndromic forms of autosomal-recessive congenital ichthyosis (ARCI). However, not all genetic causes for ARCI have been discovered to date. Using whole-exome sequencing (WES) and multigene panel screening, we identified 6 ARCI-affected individuals from three unrelated families with mutations in Sulfotransferase family 2B member 1 (SULT2B1), showing their causative association with ARCI. Cytosolic sulfotransferases form a large family of enzymes that are involved in the synthesis and metabolism of several steroids in humans. We identified four distinct mutations including missense, nonsense, and splice site mutations. We demonstrated the loss of SULT2B1 expression at RNA and protein levels in keratinocytes from individuals with ARCI by functional analyses. Furthermore, we succeeded in reconstructing the morphologic skin alterations in a 3D organotypic tissue culture model with SULT2B1-deficient keratinocytes and fibroblasts. By thin layer chromatography (TLC) of extracts from these organotypic cultures, we could show the absence of cholesterol sulfate, the metabolite of SULT2B1, and an increased level of cholesterol, indicating a disturbed cholesterol metabolism of the skin upon loss-of-function mutation in SULT2B1. In conclusion, our study reveals an essential role for SULT2B1 in the proper development of healthy human skin. Mutation in SULT2B1 leads to an ARCI phenotype via increased proliferation of human keratinocytes, thickening of epithelial layers, and altered epidermal cholesterol metabolism.
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Project description:Structure-function implication on a novel homozygous Trp250/Gly mutation of transglutaminase-1 (TGM1) observed in a patient of autosomal recessive congenital ichthyosis is invoked from a bioinformatics analysis. Structural consequences of this mutation are hypothesized in comparison to homologous enzyme human factor XIIIA accepted as valid in similar structural analysis and are projected as guidelines for future studies at an experimental level on TGM1 thus mutated.
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Project description:Autosomal recessive congenital ichthyosis (ARCI) is a rare form of keratinization disorder of the skin, which can be caused by mutations in 14 ARCI genes. We present a rare case of ARCI that carried a novel null mutation and a novel splice site mutation in the CYP4F22 gene.
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Project description:Numerous genetic conditions give rise to a scaly skin phenotype as a result of impaired barrier function. Differences in appearance suggest the response of epidermal cells depends upon the basic defect. The present work characterizes the departure of afflicted corneocytes from normal as judged by their proteomic profiles in three types of autosomal recessive congenital ichthyosis arising from defects in the genes PNPLA1, SDR9C7 and TGM1. The results show that the profiles were distinctive, each displaying a set of altered protein levels, but with a subset of common alterations. Departure from the normal profile was examined at three different anatomic sites (forearm, forehead, leg). Reflecting that the normal protein profile differed at these sites, comparing profiles from afflicted subjects revealed that the alterations in profile were site-dependent. These results suggest proteomic profiling can provide a quantitative measure of departure from the normal state of epidermis. Further development may find application to diagnosis, including identification of new genetic defects, and may help understand signaling pathways perturbed by the basic defects, supplementing visual evaluation of treatment.
2018-08-17 | MSV000082828 | MassIVE
Project description:There are at least 38 mutant genes known to be associated with the ichthyosis phenotypes, and autosomal recessive congenital ichthyosis (ARCI) is a specific subgroup caused by mutations in 13 different genes. Mutations in some of these genes, such as CERS3 with only two previous reports, are rare. In this study, we identified mutations in candidate genes in consanguineous families with ARCI with a next generation sequencing (NGS) array that incorporates 38 ichthyosis associated genes. We applied this sequencing array to DNA from 140 ichthyosis families with high prevalence of consanguinity. Among these patients we identified six distinct, previously unreported mutations in CERS3 in six Iranian families. These mutations in each family co-segregated with the ichthyosis phenotype. The patients demonstrated collodion membrane at birth, acrogeria, generalized scaling, and hyperlinearity of the palms and soles. The presence of a significant percentage of CERS3 mutations in our cohort depicts a marked difference between the etiology of ichthyoses in genetically poorly characterized regions and well-characterized western populations. Also, it shows that rare alleles are more prevalent in the gene pool of consanguineous populations and emphasizes the importance of these population studies for better understanding of ichthyosis pathogenesis.
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Project description:Autosomal recessive congenital ichthyosis (ARCI) is a rare heterogeneous keratinization disorder of the skin. It is clinically divided into 2 subtypes, lamellar ichthyosis (LI) and congenital ichthyosiformis erythroderma (CIE). We investigated forty-three ARCI Egyptian individuals in 16 severe LI, and 10 CIE families. We identified 5 alleles in two Egyptian families as having intron-5/exon-6 splice acceptor mutation recognized by the MspI restriction endonuclease. This promoted to a frequency of 9.6% for this mutation (5 splice-mutation alleles/52 alleles tested). We extended our previous dataset to update the detection of R142H mutation in 4 CIE Egyptian families and one LI phenotype (frequency of 28.8%; 15/52), whereas we still had no R141H among our Egyptian population. There was no correlation between phenotype and genotype in our study. Surprisingly, the mutant alleles detected in intron-5 acceptor splice-site were associated with the other extreme of CIE phenotypes rather than the severe LI form. We clearly demonstrated that the ARCI Egyptian families in Upper Egypt was ethnically pure and had a tendency not to be a hybrid with other populations in Lower Egypt, Delta zone and Cairo city.
| S-EPMC3839340 | biostudies-other
Project description:Mutations in genes such as transglutaminase-1 (TGM1), which are responsible for the formation and normal functioning of a lipid barrier, lead to the development of autosomal recessive congenital ichthyosis (ARCI). ARCIs are characterized by varying degrees of hyperkeratosis and the presence of scales on the body surface since birth. The quality of life of patients is often significantly affected, and in order to alleviate the manifestations of the disease, symptomatic therapy with moisturizers, keratolytics, retinoids and other cosmetic substances is often used to improve the condition of the patients' skin. Graft transplantation is commonly used to correct defects of the eye. However, these approaches offer symptomatic treatment that does not restore the lost protein function or provide a long-term skin barrier. Gene and cell therapies are evolving as promising therapy for ARCIs that can correct the functional activity of altered proteins. However, these approaches are still at an early stage of development. This review discusses current studies of gene and cell therapy approaches for various types of ichthyosis and their further prospects for patient treatment.
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Project description:A minority of patients with nonsyndromic autosomal recessive congenital ichthyosis (ARCI) display mutations in NIPAL4 (ICHTHYIN). This protein plays a role in epidermal lipid metabolism, although the mechanism is unknown. The study describes a moderate form of ARCI in an extended pedigree of American Bulldogs that is linked to the gene encoding ichthyin. The gross phenotype was manifest as a disheveled pelage shortly after birth, generalized scaling, and adherent brown scale with erythema of the abdominal skin. Pedigree analysis indicated an autosomal recessive mode of inheritance. Ultrastructurally, the epidermis showed discontinuous lipid bilayers, unprocessed lipid within corneocytes, and abnormal lamellar bodies. Linkage analysis, performed by choosing simple sequence repeat markers and single-nucleotide polymorphisms near genes known to cause ACRI, revealed an association with NIPAL4. NIPAL4 was identified and sequenced using standard methods. No mutation was identified within the gene, but affected dogs had a SINE element 5' upstream of exon 1 in a highly conserved region. Of 545 DNA samples from American Bulldogs, 32 dogs (17 females, 15 males) were homozygous for the polymerase chain reaction fragment. All affected dogs were homozygous, with parents heterozygous for the insertion. Immunolabeling revealed an absence of ichthyin in the epidermis. This is the first description of ARCI associated with decreased expression of NIPAL4 in nonhuman species.
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