The enzyme responsible for conversion of all-transretinol into retinyl esters, the lecithin retinol acyltransferase (LRAT) has been characterized at the molecular level. The cDNA coding for this protein was cloned and its amino acid sequence deduced. LRAT is composed of a polypeptide of 230 amino acid residues with a calculated mass of 25.3 kDa. Tissue distribution analysis by Northern blot showed expression of a 5.0-kilobase transcript in the human retinal pigment epithelium as well as in other tissues that are known for their high LRAT activity and vitamin A processing. Affinity labeling experiments using specific compounds with high affinity for LRAT and monospecific polyclonal antibodies raised in rabbits against two peptide sequences for LRAT confirmed the molecular mass of LRAT as a 25-kDa protein. Vitamin A (retinol) is the substrate for the biosynthesis of several functional retinoids (retinol derivatives) which are essential for important biological processes such as, vision, reproduction, and development (for review, see Ref. 1). The small intestinal epithelium is the first site of interaction and processing of retinol after absorption from the diet. Within this epithelium, the final processing step involves the esterification of retinol with long chain fatty acids, primarily palmitic, and incorporation of the retinyl esters into the hydrophobic core of chylomicrons which are secreted into the lymph and ultimately enter the blood via the thoracic and other lymphatic ducts (2). Chylomicron remnants are taken up by the liver and the retinyl esters are stored until needed. Following de-esterification by the liver, retinol is complexed with a 21-kDa retinol-binding protein (RBP) 1 and secreted into the circulation as a complex with transthyretin whereby it is distributed to other tissues (3). Both proteins are thought to transport and protect retinol from oxidation and/or isomerization during the distribution process. In the eye, and more specifically in the retinal pigment epithelium (RPE), this retinol complex interacts with the basal membrane of RPE cells probably via an RBP receptor (4, 5), where retinol is delivered into the cytoplasm to initiate a unique and highly specialized process for the RPE, the visual cycle (for review, see Refs. 6 -8). During this important process, the retinol bound to a cellular retinol-binding protein (CRBP), is trans-esterified by an enzyme named lecithin retinol acyltransferase (LRAT) (9 -11) that transfers an acyl group from lecithin to retinol to generate all-trans-retinyl esters. All-trans-retinyl esters generated by the activity of LRAT are not only presumptive storage forms of vitamin A, but they are also substrates for an isomerohydrolase which transforms the esters into an intermediate 11-cis-retinol (12, 13). Due to a membrane-associated alcohol dehydrogenase (14, 15), 11-cis-retinol is then oxidized and converted into 11-cis-retinaldehyde which is the chromophore for rhodopsin and the cone photopigments. In the RPE, the esterification process of retinol by LRA...
Background: Porokeratosis is associated with mevalonate pathway gene mutations. Therapeutic options are few and often limited in efficacy.Objective: On the basis of preventing the accumulation of toxic metabolites while replenishing essential end-products, we studied the efficacy of topical lovastatin/cholesterol in different variants of porokeratosis.Methods: A series of 5 patients with disseminated superficial actinic porokeratosis (DSAP,n=1), porokeratosis palmaris et plantaris disseminata (PPPD,n=2) and linear porokeratosis (LP,n=2) were enrolled. Patients were genotyped prior to initiation of therapy and then applied topical lovastatin/cholesterol twice daily to a unilateral defined treatment area for up to 3 months. Response was evaluated and patients were photographed every visit.Results: Three patients had MVD mutations and 2 patients had PMVK mutations. Treatment with topical lovastatin/cholesterol (but not cholesterol alone) resulted in near complete clearance of DSAP lesions after 4 weeks of therapy, and moderate improvement of lesions in PPPD and LP. There were no adverse events.Limitations: Case series design with a small number of patients. Conclusion:Topical cholesterol/lovastatin is a safe and effective therapy for porokeratosis that underscores the utility of a pathogenesis-based therapies which replace deficient end-products and prevent accumulation of potentially toxic precursors.
Vascular tumors are among the most common neoplasms in infants and children; 5%-10% of newborns present with or develop lesions within the first 3 months of life. Most are benign infantile hemangiomas that typically regress by 5 years of age; other vascular tumors include congenital tufted angiomas (TAs), kaposiform hemangioendotheliomas (KHEs), and childhood lobular capillary hemangiomas (LCHs). Some of these lesions can become locally invasive and unresponsive to pharmacologic intervention, leading to significant complications. Recent investigation has revealed that activating mutations in HRAS, KRAS, NRAS, GNAQ, and GNA11 can cause certain types of rare childhood vascular tumors, and we have now identified causal recurrent somatic activating mutations in GNA14 by whole-exome and targeted sequencing. We found somatic activating GNA14 c.614A>T (p.Gln205Leu) mutations in one KHE, one TA, and one LCH and a GNA11 c.547C>T (p.Arg183Cys) mutation in two LCH lesions. We examined mutation pathobiology via expression of mutant GNA14 or GNA11 in primary human endothelial cells and melanocytes. GNA14 and GNA11 mutations induced changes in cellular morphology and rendered cells growth-factor independent by upregulating the MAPK pathway. Our findings identify GNA14 mutations as a cause of childhood vascular tumors, offer insight into mechanisms of oncogenic transformation by mutations affecting Gaq family members, and identify potential targets for therapeutic intervention.
Resveratrol exhibits a potent antimicrobial activity. However, the mechanism underlying its antibacterial activity has not been shown. In this study, the antibacterial mechanism of resveratrol was investigated. To investigate induction of the SOS response, a strain containing the lacZ+gene under the control of an SOS-inducible sulA promoter was constructed. DNA damage was measured by pulse-field gel electrophoresis (PFGE). After resveratrol treatment, the cells were observed by confocal microscopy. For the RNA silencing assay, ftsZ-specific antisense peptide nucleic acid (PNA) was used. Reactive oxygen species (ROS) production increased in Escherichia coli after resveratrol treatment; however, cell growth was not recovered by ROS quenching, indicating that, in this experiment, ROS formation and cell death following resveratrol treatment were not directly correlated. Resveratrol treatment increased DNA fragmentation in cells, while SOS response-related gene expression levels increased in a dose-dependent manner. Cell elongation was observed after resveratrol treatment. Elongation was induced by inhibiting FtsZ, an essential cell-division protein in prokaryotes, and resulted in significant inhibition of Z-ring the formation in E. coli. The expression of ftsZ mRNA was suppressed by resveratrol. Our results indicate that resveratrol inhibits bacterial cell growth by suppressing FtsZ expression and Z-ring formation.
This study provides evidence that Asian dust events are impacting on the respiratory symptoms of subjects with bronchial asthma, and ambient air pollution, particularly elevated PM(10), might be one of the aggravating factors.
Pathologically elevated serum levels of fibroblast growth factor-23 (FGF23), a bone-derived hormone that regulates phosphorus homeostasis, result in renal phosphate wasting and lead to rickets or osteomalacia. Rarely, elevated serum FGF23 levels are found in association with mosaic cutaneous disorders that affect large proportions of the skin and appear in patterns corresponding to the migration of ectodermal progenitors. The cause and source of elevated serum FGF23 is unknown. In those conditions, such as epidermal and large congenital melanocytic nevi, skin lesions are variably associated with other abnormalities in the eye, brain and vasculature. The wide distribution of involved tissues and the appearance of multiple segmental skin and bone lesions suggest that these conditions result from early embryonic somatic mutations. We report five such cases with elevated serum FGF23 and bone lesions, four with large epidermal nevi and one with a giant congenital melanocytic nevus. Exome sequencing of blood and affected skin tissue identified somatic activating mutations of HRAS or NRAS in each case without recurrent secondary mutation, and we further found that the same mutation is present in dysplastic bone. Our finding of somatic activating RAS mutation in bone, the endogenous source of FGF23, provides the first evidence that elevated serum FGF23 levels, hypophosphatemia and osteomalacia are associated with pathologic Ras activation and may provide insight in the heretofore limited understanding of the regulation of FGF23.
IMPORTANCE Linear porokeratosis features linear and whorled configurations of keratotic papules and plaques, with coronoid lamellae present on histologic examination. Because linear porokeratosis manifests in the lines of Blaschko representing the dorsoventral migration patterns of keratinocyte precursors, it has been suggested that postzygotic somatic mutation underlies the disease. However, no genetic evidence has supported this hypothesis to date. OBJECTIVE To identify genetic mutations associated with linear porokeratosis. DESIGN, SETTING, AND PARTICIPANTS Paired whole-exome sequencing of affected skin and blood/saliva samples from 3 participants from 3 academic medical centers with clinical and histologic diagnoses of linear porokeratosis. INTERVENTIONS OR EXPOSURES Whole-exome sequencing of paired blood/saliva and affected tissue samples isolated from linear porokeratosis lesions. MAIN OUTCOMES AND MEASURES Germline and somatic genomic characteristics of participants with linear porokeratosis. RESULTS Of the 3 participants, 2 were male. Participant ages ranged from 5 to 20 years old. We found a combination of a novel germline mutation and a novel somatic mutation within affected tissue in all cases. One participant had a germline heterozygous PMVK c.329G>A mutation and a somatic copy-neutral loss of heterozygosity confined to the lesional skin, while a second had a germline heterozygous PMVK c.79G>T mutation and an additional PMVK c.379C>T mutation in the lesional skin. In a third participant, there was a germline splice-site mutation in MVD (c.70 + 5G>A) and a somatic deletion in MVD causing frameshift and premature codon termination within the lesional skin (c.811_815del, p.F271Afs*33 frameshift). CONCLUSIONS AND RELEVANCE Our findings suggest that linear porokeratosis is associated with the presence of second-hit postzygotic mutations in the genes that encode enzymes within the mevalonate biosynthesis pathway, and provide further evidence that the mevalonate pathway may be a potential target for therapeutic intervention in porokeratosis.
Importance: Genetic testing results can provide guidance in developing personalized treatment plans for patients with vascular anomalies.Objective: To explore the efficacy of tramitinib in the treatment of an extracranial arteriovenous malformation with a somatic MAP2K1 mutation.Design: Case report of a child with an arteriovenousu malformation that was successfully treated with trametinib after identification of a specific somatic mutation within the malformation.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.