-
Genes Mar 2023Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin. The three major...
Autosomal recessive congenital ichthyosis (ARCI) is a non-syndromic congenital disorder of cornification characterized by abnormal scaling of the skin. The three major phenotypes are lamellar ichthyosis, congenital ichthyosiform erythroderma, and harlequin ichthyosis. ARCI is caused by biallelic mutations in , , , , , , , , , and . The most severe form of ARCI, harlequin ichthyosis, is caused by mutations in . Mutations in this gene can also lead to congenital ichthyosiform erythroderma or lamellar ichthyosis. We present a large cohort of 64 patients affected with ARCI carrying biallelic mutations in . Our study comprises 34 novel mutations in , expanding the mutational spectrum of -associated ARCI up to 217 mutations. Within these we found the possible mutational hotspots c.4541G>A, p.(Arg1514His) and c.4139A>G, p.(Asn1380Ser). A correlation of the phenotype with the effect of the genetic mutation on protein function is demonstrated. Loss-of-function mutations on both alleles generally result in harlequin ichthyosis, whereas biallelic missense mutations mainly lead to CIE or LI.
Topics: Humans; Ichthyosis, Lamellar; Genes, Recessive; Mutation; Ichthyosiform Erythroderma, Congenital; Genetic Association Studies; ATP-Binding Cassette Transporters; Acyltransferases; Phospholipases
PubMed: 36980989
DOI: 10.3390/genes14030717 -
Paediatric Anaesthesia Dec 2020Sjögren-Larsson syndrome is a rare inherited neurocutaneous disorder characterized by congenital ichthyosis, spasticity, intellectual disability, seizures, and...
BACKGROUND
Sjögren-Larsson syndrome is a rare inherited neurocutaneous disorder characterized by congenital ichthyosis, spasticity, intellectual disability, seizures, and ophthalmologic changes. Most individuals with Sjögren-Larsson syndrome live well into adulthood and often require surgical intervention to manage their symptomatology.
AIMS
The aim of this work was to review the clinical aspects of Sjögren-Larsson syndrome, highlight the unique anesthetic considerations associated with this disease, and provide practical recommendations about anesthetic management.
METHODS
A retrospective case review from February 2013 to October 2019 was performed based on subject participation in a Sjögren-Larsson syndrome longitudinal study at the University of Nebraska Medical Center. Anesthetic and surgical records were reviewed for the following data: age, sex, relevant comorbid conditions, anesthetic induction and maintenance agents, intravenous and oral analgesics, muscle relaxants, and anesthetic-related complications.
RESULTS
Fourteen patients with Sjögren-Larsson syndrome undergoing 48 anesthetic events were identified. A variety of anesthetic techniques was utilized. No serious adverse events were encountered. The most common clinical observations were related to the ichthyosis seen in Sjögren-Larsson syndrome, which led to difficulty in adherence of electrocardiogram leads and intravenous catheter dressings.
CONCLUSIONS
We found that anesthesia can be safely administered in patients with Sjögren-Larsson syndrome. Providers should be aware of anesthetic management issues in Sjögren-Larsson syndrome including challenges placing and securing lines and monitors secondary to the ichthyosis.
Topics: Adult; Anesthetics; Humans; Intellectual Disability; Longitudinal Studies; Retrospective Studies; Sjogren-Larsson Syndrome
PubMed: 33037729
DOI: 10.1111/pan.14034 -
The Journal of Investigative Dermatology Jan 2021Atopic dermatitis (AD) is an inflammatory skin disease in which epidermal barrier impairment, often owing to FLG null mutations, precedes immune hyperresponsiveness....
Atopic dermatitis (AD) is an inflammatory skin disease in which epidermal barrier impairment, often owing to FLG null mutations, precedes immune hyperresponsiveness. Ichthyosis vulgaris is characterized by FLG null mutations and noninflamed dry skin. Netherton syndrome (NS), caused by SPINK5 null mutations, is characterized by generalized erythroderma with scaling and atopic manifestations. The goal of this work was to evaluate associations between specific skin disease features, such as ichthyotic and/or atopic manifestations, and the skin bacterial and fungal microbiota. Taxon diversity showed greater variation in the bacterial microbiota than in the fungal microbiota in the skin diseases. The relative abundances of Firmicutes (Staphylococcus) and Actinobacteria (Corynebacterium) were augmented in ichthyosis vulgaris, AD, and NS, whereas those of Proteobacteria/Enhydrobacter and Bacteroidetes were reduced, regardless of body site. Furthermore, proportions of Staphylococcus were correlated with transepidermal water loss and serum IgE levels. Nevertheless, the skin of patients with low to mild AD was overcolonized with Staphylococcus epidermidis and not with Staphylococcus aureus. Ascomycota were increased in both AD and NS, but from expansion of different fungal species. Finally, the expansion of pathologic bacteria in AD and NS might be supported by surrounding fungi. Thus, distinguishable bacterial and fungal skin dysbiosis in AD, NS, and ichthyosis vulgaris emphasizes disease-specific pathomechanisms.
Topics: Adult; Bacteria; Dermatitis, Atopic; Dysbiosis; Female; Filaggrin Proteins; Fungi; Humans; Male; Microbiota; Netherton Syndrome; Skin
PubMed: 32553662
DOI: 10.1016/j.jid.2020.05.102 -
The Journal of Investigative Dermatology Apr 2017
Topics: Arachidonate 12-Lipoxygenase; Humans; Ichthyosis; Oxidoreductases
PubMed: 28011144
DOI: 10.1016/j.jid.2016.12.008 -
Yakugaku Zasshi : Journal of the... 2017The primary function of the skin is to act as a permeability barrier that prevents water loss from inside the body and external invasion such as by pathogens, harmful... (Review)
Review
The primary function of the skin is to act as a permeability barrier that prevents water loss from inside the body and external invasion such as by pathogens, harmful substances, and allergens. Lipids play a critical role in skin barrier formation by forming multi-lamellar structures in the stratum corneum, the outermost cell layer of the epidermis. Ceramide, the backbone of sphingolipids, accounts for more than 50% of the stratum corneum lipids. Acylceramides are epidermis-specific ceramide species essential for skin barrier formation. Decreases in acylceramide levels and changes in ceramide composition and chain-length are associated with such cutaneous disorders as ichthyosis, atopic dermatitis, and psoriasis. Acylceramide consists of a long-chain base and an amide-linked ultra-long-chain fatty acid (ULCFA, 28-36 carbon chain), which is ω-hydroxylated and esterified with linoleic acid. Although the molecular mechanism by which acylceramide is generated has not been fully understood for decades, we recently identified two genes, CYP4F22 and PNPLA1, involved in acylceramide synthesis and elucidated the entire biosynthetic pathway of acylceramide: the synthesis of ULCFA by ELOVL1 and ELOVL4, ω-hydroxylation of the ULCFA by CYP4F22, amide-bond formation with a long-chain base by CERS3, and transacylation of linoleic acid from triacylglycerol to ω-hydroxyceramide by PNPLA1 to generate acylceramide. CYP4F22 and PNPLA1 are the causative genes of ichthyosis. We demonstrated that mutations of CYP4F22 or PNPLA1 markedly reduced acylceramide production. Our recent findings provide important insights into the molecular mechanisms of skin barrier formation and of ichthyosis pathogenesis.
Topics: Animals; Cell Membrane Permeability; Ceramides; Cytochrome P-450 Enzyme System; Epidermal Cells; Epidermis; Humans; Ichthyosis; Lipase; Mice; Mutation; Skin Physiological Phenomena
PubMed: 28966260
DOI: 10.1248/yakushi.17-00126 -
Journal of Lipid Research Apr 2023Sphingosine 1-phosphate lyase (SGPL1) insufficiency (SPLIS) is a syndrome which presents with adrenal insufficiency, steroid-resistant nephrotic syndrome,...
Sphingosine 1-phosphate lyase (SGPL1) insufficiency (SPLIS) is a syndrome which presents with adrenal insufficiency, steroid-resistant nephrotic syndrome, hypothyroidism, neurological disease, and ichthyosis. Where a skin phenotype is reported, 94% had abnormalities such as ichthyosis, acanthosis, and hyperpigmentation. To elucidate the disease mechanism and the role SGPL1 plays in the skin barrier we established clustered regularly interspaced short palindromic repeats-Cas9 SGPL1 KO and a lentiviral-induced SGPL1 overexpression (OE) in telomerase reverse-transcriptase immortalised human keratinocytes (N/TERT-1) and thereafter organotypic skin equivalents. Loss of SGPL1 caused an accumulation of S1P, sphingosine, and ceramides, while its overexpression caused a reduction of these species. RNAseq analysis showed perturbations in sphingolipid pathway genes, particularly in SGPL1_KO, and our gene set enrichment analysis revealed polar opposite differential gene expression between SGPL1_KO and _OE in keratinocyte differentiation and Ca signaling genesets. SGPL1_KO upregulated differentiation markers, while SGPL1_OE upregulated basal and proliferative markers. The advanced differentiation of SGPL1_KO was confirmed by 3D organotypic models that also presented with a thickened and retained stratum corneum and a breakdown of E-cadherin junctions. We conclude that SPLIS associated ichthyosis is a multifaceted disease caused possibly by sphingolipid imbalance and excessive S1P signaling, leading to increased differentiation and an imbalance of the lipid lamellae throughout the epidermis.
Topics: Humans; Sphingolipids; Calcium; Aldehyde-Lyases; Lysophospholipids; Sphingosine; Ichthyosis
PubMed: 36868360
DOI: 10.1016/j.jlr.2023.100351 -
International Journal of Molecular... Mar 2021Glycine is an amino acid with unique properties because its side chain is composed of a single hydrogen atom. It confers conformational flexibility to proteins and... (Review)
Review
Glycine is an amino acid with unique properties because its side chain is composed of a single hydrogen atom. It confers conformational flexibility to proteins and conserved glycines are often indicative of protein domains involving tight turns or bends. All six beta-type connexins expressed in human epidermis (Cx26, Cx30, Cx30.3, Cx31, Cx31.1 and Cx32) contain a glycine at position 12 (G12). G12 is located about halfway through the cytoplasmic amino terminus and substitutions alter connexin function in a variety of ways, in some cases altering protein interactions and leading to cell death. There is also evidence that alteration of G12 changes the structure of the amino terminus in connexin- and amino acid- specific ways. This review integrates structural, functional and physiological information about the role of G12 in connexins, focusing on beta-connexins expressed in human epidermis. The importance of G12 substitutions in these beta-connexins is revealed in two hereditary skin disorders, keratitis ichthyosis and erythrokeratodermia variabilis, both of which result from missense mutations affecting G12.
Topics: Amino Acid Substitution; Connexins; Epidermis; Erythrokeratodermia Variabilis; Gap Junctions; Glycine; Humans; Ichthyosis; Mutation, Missense
PubMed: 33807656
DOI: 10.3390/ijms22052615 -
Journal of Child Neurology Oct 2021Sjögren-Larsson syndrome (SLS) is a rare neurologic disorder caused by pathogenic sequence variants in and characterized by ichthyosis, spasticity, intellectual...
Sjögren-Larsson syndrome (SLS) is a rare neurologic disorder caused by pathogenic sequence variants in and characterized by ichthyosis, spasticity, intellectual disability, and a crystalline retinopathy. Neurologic symptoms develop in the first 2 years of life. Except for worsening ambulation due to spastic diplegia and contractures, the neurologic disease has been considered static and a neurodegenerative course is distinctly unusual. We describe a young child with Sjögren-Larsson syndrome who exhibited an early and severely progressive neurologic phenotype that may have been triggered by a febrile rotavirus infection. Together with 7 additional published cases of these atypical patients, we emphasize that a neurodegenerative course can be an extreme outcome for a minority of patients with Sjögren-Larsson syndrome.
Topics: Child; Child, Preschool; Female; Humans; Neurodegenerative Diseases; Phenotype; Rotavirus Infections; Sjogren-Larsson Syndrome
PubMed: 34315315
DOI: 10.1177/08830738211029390 -
Journal of Lipid Research Jun 2023Loss-of-function mutations in patatin-like phospholipase domain-containing protein 1 (PNPLA1) cause autosomal recessive congenital ichthyosis, and altered PNPLA1...
Loss-of-function mutations in patatin-like phospholipase domain-containing protein 1 (PNPLA1) cause autosomal recessive congenital ichthyosis, and altered PNPLA1 activity is implicated in the pathogenesis of atopic dermatitis and other common skin diseases. To examine the hypothesis that PNPLA1 catalyzes the synthesis of acylceramides and acyl acids, we expressed and partially purified a soluble, truncated form of PNPLA1 in Escherichia coli, (PNPLA1) along with the related protein PNPLA2 (ATGL, adipose triglyceride lipase) and coactivator CGI-58. Liposomal substrates were incubated with recombinant enzymes for 0.5-24 h and products analyzed by HPLC-UV and LC-MS. Using trilinolein or dilinolein substrates, PNPLA1, like ATGL, catalyzed lipolysis and acyltransferase reactions with 2-30% conversion into linoleic acid, monolinolein, and trilinolein. CGI-58 enhanced ATGL-catalyzed lipolysis as previously reported, but transacylase activity was not enhanced with ATGL or PNPLA1. In matching the proposed activity in vivo, PNPLA1 catalyzed acyl transfer from trilinolein and dilinolein donors to omega-hydroxy ceramide, omega-hydroxy glucosylceramide, and omega-hydroxy acid acceptors to form acylceramide, glucosyl-acylceramide, and acyl acid, respectively, albeit with only ∼0.05% conversion of the substrates. Notably, in experiments comparing dilinolein vs. diolein acyl donors, PNPLA1 transferred linoleate with 3:1 selectivity over oleate into acylceramide. These results support the role for PNPLA1 in the synthesis of acylceramides and acyl acids in epidermis and suggest that the enrichment of these lipids with linoleic acid could result from the substrate selectivity of PNPLA1.
Topics: Humans; Skin; Linoleic Acid; Lipase; Epidermis; Ichthyosis, Lamellar; Ceramides; Acyltransferases; Phospholipases
PubMed: 37087101
DOI: 10.1016/j.jlr.2023.100379 -
Journal of Cutaneous Pathology Jun 2020Epidermolytic acanthoma (EA) is a rare acquired lesion demonstrating a characteristic histopathological pattern of epidermal degeneration referred to as epidermolytic...
BACKGROUND
Epidermolytic acanthoma (EA) is a rare acquired lesion demonstrating a characteristic histopathological pattern of epidermal degeneration referred to as epidermolytic hyperkeratosis (EHK). On histopathological analysis, EA appears nearly identical to inherited EHK-associated dermatoses such as epidermolytic ichthyosis and ichthyosis bullosa of Siemens. While it has been speculated that EA is caused by mutations in KRT10, KRT1, or KRT2 found in these inherited dermatoses, none have yet been identified. Herein, we aim to identify the contributions of keratin mutations to EA.
METHODS
Using genomic DNA extracted from paraffin-embedded samples from departmental archives, we evaluated a discovery cohort using whole-exome sequencing (WES) and assessed remaining samples using Sanger sequencing screening and restriction fragment length polymorphism (RFLP) analysis.
RESULTS
DNA from 16/20 cases in our sample was of sufficient quality for polymerase chain reaction amplification. WES of genomic DNA from lesional tissue revealed KRT10 c.466C > T, p.Arg156Cys mutations in 2/3 samples submitted for examination. RFLP analysis of these samples as well as eight additional samples confirmed the mutations identified via WES and identified four additional cases with Arg156 mutations. In sum, 6/11 screened cases showed hotspot mutation in KRT10.
CONCLUSIONS
Hotspot mutations in the Arg156 position of KRT10, known to cause epidermolytic ichthyosis, also underlie EA.
Topics: Acanthoma; Adult; Aged; Aged, 80 and over; Female; Genomics; Humans; Hyperkeratosis, Epidermolytic; Ichthyosis Bullosa of Siemens; Keratin-10; Keratins; Male; Middle Aged; Mutation; Skin Neoplasms; Exome Sequencing
PubMed: 32045015
DOI: 10.1111/cup.13664