The Experts below are selected from a list of 90 Experts worldwide ranked by ideXlab platform
Hiroshi Shimizu - One of the best experts on this subject based on the ideXlab platform.
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Partially disturbed Lamellar Granule secretion in mild congenital ichthyosiform erythroderma with ALOX12B mutations.
The British journal of dermatology, 2010Co-Authors: Masashi Akiyama, Kaori Sakai, Teruki Yanagi, N. Tabata, M. Yamada, Hiroshi ShimizuAbstract:Congenital ichthyosiform erythroderma (CIE) (OMIM 242100) is a major type of autosomal recessive congenital ichthyosis (ARCI) showing generalized scaling and erythroderma without blister formation. 1 Mutations in ALOX12B (OMIM 603741), encoding 12R-lipoxygenase (LOX), were identified in patients with CIE in 2002. 2 To date, several ALOX12B mutations have been reported in CIE families. 3,4 LOXs are a family of nonhaem, iron-containing dioxygenases which catalyse dioxygenation of fatty acids with one or more (Z,Z)-1,4-pentadiene moieties. 5 Three members of the human LOX family, 15-LOX-2, 12R-LOX and eLOX-3, are preferentially expressed in the skin. 5,6 The 12R-LOX pathway leads to hepoxilin B3 and trioxilin B3 7 resulting in 20-carboxy-trioxilin A3, 5 which is thought to be a key biological regulator in the skin. 8 12R-LOX deficiency results in a CIE phenotype in humans 2,9,10 and in mice 11,12 We report that a Japanese patient with CIE, harbouring one previously unreported ALOX12B mutation p.Arg442Gln and another known mutation p.Arg432X, showed partially disturbed secretion of Lamellar Granule (LG) contents in the epidermis.
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harlequin ichthyosis model mouse reveals alveolar collapse and severe fetal skin barrier defects
Human Molecular Genetics, 2008Co-Authors: Teruki Yanagi, Masashi Akiyama, Kaori Sakai, Hiroshi Nishihara, Wataru Nishie, Shinya Tanaka, Hiroshi ShimizuAbstract:: Harlequin ichthyosis (HI), which is the most severe genodermatosis, is caused by loss-of-function mutations in ABCA12, a member of the ATP-binding cassette transporter family. To investigate the pathomechanism of HI and the function of the ABCA12 protein, we generated ABCA12-deficient mice (Abca12(-/-)) by targeting Abca12. Abca12(-/-) mice closely reproduce the human HI phenotype, showing marked hyperkeratosis with eclabium and skin fissure. Lamellar Granule abnormalities and defective ceramide distribution were remarkable in the epidermis. Skin permeability assay of Abca12(-/-) fetuses revealed severe skin barrier dysfunction after the initiation of keratinization. Surprisingly, the Abca12(-/-) mice also demonstrated lung alveolar collapse immediately after birth. Lamellar bodies in alveolar type II cells of the Abca12(-/-) mice lacked normal Lamellar structures. The level of surfactant protein B, an essential component of alveolar surfactant, was reduced in the Abca12(-/-) mice. Fetal therapeutic trials with systemic administration of retinoid or dexamethasone, which are effective for HI and respiratory distress, respectively, to the pregnant mother mice neither improved the skin phenotype nor extended the survival period. Our HI model mice reproduce the human HI skin phenotype soon after the initiation of fetal skin keratinization and provide evidence that ABCA12 plays pivotal roles in lung and skin barrier functions.
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Localization of ABCA12 from Golgi apparatus to Lamellar Granules in human upper epidermal keratinocytes
Experimental dermatology, 2007Co-Authors: Kaori Sakai, Masashi Akiyama, Yoriko Sugiyama-nakagiri, James R. Mcmillan, Daisuke Sawamura, Hiroshi ShimizuAbstract:ABCA12 is an ATP-binding cassette transporter and is thought to act as a transmembrane lipid transporter. We reported that deleterious ABCA12 mutations cause a disturbance in Lamellar Granule (LG) lipid transport in the epidermal granular layer keratinocytes, resulting in harlequin ichthyosis, a severe genodermatosis. Detailed localization of ABCA12 in comparison with glucosylceramide and Golgi apparatus markers were studied in order to obtain clues to clarify the function(s) of ABCA12 in human skin. We performed double-labelling immunofluorescent staining using antibodies against ABCA12, glucosylceramide and two Golgi apparatus markers (TGN46 and GM130) in normal human skin and cultured keratinocytes. Immunogold electron microscopy for ABCA12 and glucosylceramide was studied on postembedding and cryoultrathin sections of normal human skin. Confocal laser scanning microscopy demonstrated that ABCA12 and glucosylceramide co-localized in the granular layer keratinocytes as well as in keratinocytes cultured in high Ca2+ conditions through the Golgi apparatus to the cell periphery. Postembedding immunogold electron microscopy revealed that both ABCA12 and glucosylceramide labellings were associated with the LG of the uppermost granular layer keratinocytes. Using cryoultramicrotomy, Lamellar structures in the LG were more clearly observed, and ultrastructural localization of ABCA12 and glucosylceramide was better demonstrated to LG in the uppermost granular layer cells. These results indicate that ABCA12 plays an important role in lipid transport from the Golgi apparatus to LG in human granular layer keratinocytes.
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Formation of cornified cell envelope in human hair follicle development
British Journal of Dermatology, 2002Co-Authors: Masashi Akiyama, I. Matsuo, Hiroshi ShimizuAbstract:SummaryBackground Cornified cell envelope (CCE) formation is an important step in the final stage of keratinization, in which CCE precursor proteins including involucrin and loricrin are cross-linked by keratinocyte transglutaminases (TGases) to the inner surface of the plasma membrane of cornified cells, while the outer surface is coated with material derived from secreted Lamellar Granules. Objectives Skin samples from human fetuses of a series of estimated gestational age (EGA) (49–163 days) were studied for the prescence of precursor proteins. Methods TGase activity was studied by in situ TGase activity assay, and ultrastructural features of CCE formation were observed at each stage of hair follicle development. We used immunofluorescent labelling to investigate the time and site of expression of CCE precursor proteins involucrin and loricrin, TGases 1, 2 and 3, and a 25-kDa Lamellar Granule-associated protein (LGP) in developing human hair follicles. Results In the hair germ (65–84 days EGA) (corresponding to the stages 1–2 of murine hair follicle morphogenesis), only TGase 2 was observed in the entire hair germ, where in situ TGase activity was weakly positive, although thickening of cell membrane was not seen ultrastructurally. In the hair peg (85–104 days EGA) (corresponding to the stage 3 of murine hair follicle morphogenesis), loricrin and TGase 2 were seen in cells of the upper part of the hair peg while TGase 1, 3 and LGP were observed in the inner cells of the hair peg. In situ TGase activity was weakly positive in the upper part and inner cells of the hair peg. In the bulbous hair peg (105–135 days EGA) (corresponding to the stages 4–6 of murine hair follicle morphogenesis) and differentiated lanugo hair follicle (> 135 days EGA) (corresponding to the stages 7–8 of murine hair follicle morphogenesis), immunoreactivities of involucrin, loricrin, TGase 1, 2, 3, in situ TGase activity and LGP were detected in the inner root sheath cells, hair canals and inner cells of the outer root sheath in the region of the isthmus. Ultrastructurally, thickening of cell membrane was already seen in the inner root sheath cells of the bulbous hair peg and electron-dense, thick CCE was observed in the hair cuticle and hair canal of differentiated lanugo hair follicle. Conclusions These data indicate that, in terms of CCE formation, certain portions of the developing human hair follicle have already been determined in differentiation of the hair canal and cuticle at the hair peg stage.
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Periderm Cells Form Cornified Cell Envelope in Their Regression Process During Human Epidermal Development
The Journal of investigative dermatology, 1999Co-Authors: Masashi Akiyama, Lynne T. Smith, Kozo Yoneda, Karen A. Holbrook, Daniel Hohl, Hiroshi ShimizuAbstract:Terminally differentiated stratified squamous epithelium forms a lining of the plasma membrane called the cornified cell envelope, a thick layer of several covalently cross-linked precursor proteins including involucrin, small proline-rich proteins, and loricrin. Their cross-linking isodipeptide bonds are formed by epidermal transglutaminases 1-3. Material from Lamellar Granules is attached on the extracellular surface of corneocytes during the keratinization process. The formation of cornified cell envelope and sequential expression of major cornified cell envelope precursor proteins, transglutaminases, and 25 kDa Lamellar Granule-associated protein were studied in human embryonic and fetal skin. Ultrastructurally, membrane thickening has already started in periderm cells of the two-layered epidermis and an electron-dense, thickened cell envelope similar to cornified cell envelope in adult epidermis is observed in periderm cells at the three-layered and later stages of skin development. In the two-layered epidermis (49-65 d estimated gestational age), immunoreactivities of involucrin, small proline-rich proteins, all the transglutaminases, and Lamellar Granule-associated protein were present only in the periderm. In the three-layered epidermis and thereafter (66-160 d estimated gestational age), loricrin became positive in the periderm cells, transglutaminases extended to the entire epidermis, and Lamellar Granule-associated protein was detected in intermediate cells as well as periderm cells. Immunoelectron microscopy demonstrated that both major cornified cell envelope precursor proteins, involucrin and loricrin, were restricted to the cornified cell envelope in periderm cells at this stage of development. After 160 d estimated gestational age, the periderm had disappeared and cornified cell envelope proteins and Lamellar Granule-associated proteins were expressed in the spinous, granular, and cornified cells and transglutaminases were detected in the entire epidermis. These findings indicate that cornified cell envelope precursor proteins, transglutaminases, and Lamellar Granule-associated proteins are expressed in coordination in periderm cells during human epidermal development and suggest that periderm cells form cornified cell envelope in the process of regression.
Philip W. Wertz - One of the best experts on this subject based on the ideXlab platform.
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Lipid Metabolic Events Underlying the Formation of the Corneocyte Lipid Envelope.
Skin pharmacology and physiology, 2021Co-Authors: Philip W. WertzAbstract:Cornified cells of the stratum corneum have a monolayer of an unusual lipid covalently attached to the outer surface. This is referred to as the corneocyte lipid envelope (CLE). It consists of a monolayer of ω-hydroxyceramides covalently attached to the outer surface of the cornified envelope. The CLE is essential for proper barrier function of the skin and is derived from linoleate-rich acylglucosylceramides synthesized in the viable epidermis. Biosynthesis of acylglucosylceramide and its conversion to the cornified envelope is complex. Acylglucosylceramide in the bounding membrane of the Lamellar Granule is the precursor of the CLE. The acylglucosylceramide in the limiting membrane of the Lamellar Granule may be oriented with the glucosyl moiety on the inside. Conversion of the acylglucosylceramide to the CLE requires removal of the glucose by action of a glucocerebrosidase. The ester-linked fatty acid may be removed by an as yet unidentified esterase, and the resulting ω-hydroxyceramide may become ester linked to the outer surface of the cornified envelope through action of transglutaminase 1. Prior to removal of ester-linked fatty acids, linoleate is oxidized to an epoxy alcohol through action of 2 lipoxygenases. This can be further oxidized to an epoxy-enone, which can spontaneously attach to the cornified envelope through Schiff's base formation. Mutations of genes coding for enzymes involved in biosynthesis of the CLE result in ichthyosis, often accompanied by neurologic dysfunction. The CLE is recognized as essential for barrier function of skin, but many questions about details of this essentiality remain. What are the relative roles of the 2 mechanisms of lipid attachment? What is the orientation of acylglucosylceramide in the bounding membrane of Lamellar Granules? Some evidence supports a role for CLE as a scaffold upon which intercellular lamellae unfold, but other evidence does not support this role. There is also controversial evidence for a role in stratum corneum cohesion. Evidence is presented to suggest that covalently bound ω-hydroxyceramides serve as a reservoir for free sphingosine that can serve in communicating with the viable epidermis and act as a potent broad-acting antimicrobial at the skin surface. Many questions remain.
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Caveolin expression and localization in human keratinocytes suggest a role in Lamellar Granule biogenesis.
The Journal of investigative dermatology, 2003Co-Authors: G N Sando, Philip W. Wertz, H Zhu, J M Weis, J T Richman, K C MadisonAbstract:Lamellar Granules are sphingolipid-enriched organelles, probably intimately related to the tubulo-vesicular elements of the trans-Golgi network, that deliver the precursors of stratum corneum barrier lipids to the extracellular compartment. Caveolins are cholesterol-binding scaffolding proteins that facilitate the assembly of cholesterol- and sphingolipid-enriched membrane domains known as caveolae. Similarities in the composition of Lamellar Granules and caveolae suggest that caveolins could be involved in Lamellar Granule assembly, trafficking, and/or function. In order to explore this relationship, we have examined the expression of caveolins in epidermis, keratinocyte cultures, and an isolated Lamellar Granule fraction using immunolabeling, immunoblotting, and northern blotting. Several antibodies show immunolocalization of caveolin-1 in the basal layer of human epidermis, with a decline in the suprabasal layers and a reemergence of expression at the stratum granulosum/stratum corneum junction. Two of three caveolin-2 antibodies show little basal staining, but strong signal throughout the rest of the epidermis, whereas a third shows a pattern like caveolin-1. An antibody against caveolin-3 shows a strong signal at the stratum granulosum/stratum corneum interface. Caveolins partially colocalize with glucocerebrosidase, an enzyme known to be critical for remodeling of extruded Lamellar Granule contents, with AE17, a previously described Lamellar-Granule-associated antibody, and with glucosylceramides, a major lipid component of Lamellar Granules. Caveolin-1 protein is present in undifferentiated low-calcium-grown keratinocyte cultures, decreases upon induction of differentiation, and then rises to levels above those seen in undifferentiated cultures, consistent with the immunofluorescence findings. Caveolin-1 mRNA expression parallels that of the protein. Caveolin-2 mRNA and protein expression were unchanged over the course of culture differentiation. Keratinocyte caveolin-1 mRNA expression is not induced by an increase in medium calcium level and is markedly reduced by phorbol-ester-mediated protein kinase C induction. Caveolin-1 is enriched in an isolated Lamellar Granule fraction that is also enriched, as we have previously described, in lysosomal acid lipase and glucocerebrosidase, and localizes to structures consistent with Lamellar Granules on immunoelectron microscopy. The differentiation-dependent expression of caveolin-1, the colocalization of caveolins with putative Lamellar-Granule-associated antigens, their enrichment in isolated Lamellar Granules, and their presence in Lamellar-Granule-like structures on immunoelectron microscopy, along with their known structural role in the assembly of glycosphingolipid- and cholesterol-enriched domains in other cell types, suggest that caveolins may play a role in Lamellar Granule assembly, trafficking, and/or function.
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Lamellar Granule BIOGENESIS : A ROLE FOR CERAMIDE GLUCOSYLTRANSFERASE, LYSOSOMAL ENZYME TRANSPORT, AND THE GOLGI
The journal of investigative dermatology. Symposium proceedings, 1998Co-Authors: Kathi C. Madison, Donald C. Swartzendruber, Gloria N. Sando, Elizabeth J. Howard, Cheryl A. True, Delon Gilbert, Philip W. WertzAbstract:Although Lamellar Granules are critical to the formation of the epidermal permeability barrier and are a known marker of late keratinocyte differentiation, very little is known about the physiologic regulators of Lamellar Granule assembly and extrusion. Ceramide glucosyltransferase (CGT), the enzyme responsible for the synthesis of Lamellar Granule glucosylceramides (GlcCer; the precursors of the stratum corneum ceramides), is localized to the Golgi apparatus in other cell types. We have found that CGT is induced during keratinocyte culture differentiation coincident with increased GlcCer content and the appearance of Lamellar Granules. In this study we show that the differentiation-related CGT induction is likely mediated at the transcriptional level. In addition, all-trans retinoic acid, a well-known inhibitor of keratinocyte differentiation, prevents the appearance of Lamellar Granules and decreases culture CGT activity and GlcCer content without affecting sphingomyelin or total lipid content, indicating a specific inhibition of this enzymatic pathway. These data show a direct relationship between CGT activity and epidermal differentiation, suggesting that regulation of CGT expression is a critical part of epidermal barrier generation. The differentiation dependence of CGT activity, the key role of this Golgi-localized enzyme in epidermal GlcCer synthesis, and our previous finding that ceramides are converted to GlcCer in the Golgi apparatus in keratinocyte cultures, strongly suggest a Golgi origin for Lamellar Granules. In contrast to CGT, the activity of the lysosomal enzymes acid lipase and glucocerebrosidase is less clearly related to epidermal differentiation and the appearance of Lamellar Granules, although both enzymes show striking colocalization and enrichment in a subcellular Lamellar Granule fraction derived from pig epidermis. Acid lipase activity in the Lamellar Granule fraction was found to contain primarily a small lysosomal form of the enzyme, whereas total acid lipase secreted by keratinocyte cultures was found to contain a mannose-6-phosphorylated large prelysosomal form as well as a small lysosomal form. That secreted acid lipase activity is derived from both prelysosomal and lysosomal compartments suggests there may be multiple pathways by which lysosomal enzymes are secreted from keratinocytes. The combined secretion of lipid and lysosomal enzymes from Lamellar Granules places these organelles in the category of “dual-function” specialized secretory vesicles described in certain other cell types. Electron microscopic images of Lamellar Granules show shapes consistent with cross-sections of tubules or buds from tubules in addition to vesicles. These images provide evidence for the involvement of trans-Golgi network tubules and/or buds in Lamellar Granule synthesis and secretion. Journal of Investigative Dermatology Symposium Proceedings 3:80–86, 1998
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Osmium tetroxide and ruthenium tetroxide are complementary reagents for the preparation of epidermal samples for transmission electron microscopy.
The Journal of investigative dermatology, 1995Co-Authors: Donald C. Swartzendruber, I H Burnett, Philip W. Wertz, Kathi C. Madison, Christopher A. SquierAbstract:Ruthenium tetroxide and osmium tetroxide were compared as post-fixatives in the preparation of human epidermis for transmission electron microscopic examination. Both reagents revealed characteristic Lamellar Granules within the granular layer and extruded Lamellar Granule contents in the upper granular layer. The transformation of the Granule contents into multiLamellar sheets at the interface between the granular and cornified layers and the persistence of these sheets through all levels of the stratum corneum were demonstrated only with ruthenium tetroxide fixation, Therefore, the reactivity of osmium tetroxide with isolated epidermal lipids was examined. The failure of osmium tetroxide to reveal membrane structures in the stratum corneum can be explained by its inability to react with many of the lipid components of these membranes, rather than to selective removal of lipids during tissue processing, as was formerly believed. Ruthenium tetroxide, a stronger oxidizing agent than osmium tetroxide, overcomes this problem but has other severe limitations as a post-fixative.
Yoshio Hashimoto - One of the best experts on this subject based on the ideXlab platform.
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LEKTI is localized in Lamellar Granules, separated from KLK5 and KLK7, and is secreted in the extracellular spaces of the superficial stratum granulosum.
The Journal of investigative dermatology, 2005Co-Authors: Céline Deraison, Chrystelle Bonnart, R A Robinson, Emmanuelle Bitoun, Timothy O'brien, Kotaro Wakamatsu, Sawa Ohtsubo, Hidetoshi Takahashi, Yoshio HashimotoAbstract:Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is a putative serine protease inhibitor encoded by serine protease inhibitor Kazal-type 5 (SPINK5). It is strongly expressed in differentiated keratinocytes in normal skin but expression is markedly reduced or absent in Netherton syndrome (NS), a severe ichthyosis caused by SPINK5 mutations. At present, however, both the precise intracellular localization and biological roles of LEKTI are not known. To understand the functional role of LEKTI, we examined the localization of LEKTI together with kallikrein (KLK)7 and KLK5, possible targets of LEKTI, in the human epidermis, by confocal laser scanning microscopy and immunoelectron microscopy. In normal skin, LEKTI, KLK7, and KLK5 were all found in the Lamellar Granule (LG) system, but were separately localized. LEKTI was expressed earlier than KLK7 and KLK5. In NS skin, LEKTI was absent and an abnormal split in the superficial stratum granulosum was seen in three of four cases. Collectively, these results suggest that in normal skin the LG system transports and secretes LEKTI earlier than KLK7 and KLK5 preventing premature loss of stratum corneum integrity/cohesion. Our data provide new insights into the biological functions of LG and the pathogenesis of NS.
Akemi Ishida-yamamoto - One of the best experts on this subject based on the ideXlab platform.
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Marked Changes in Lamellar Granule and Trans-Golgi Network Structure Occur during Epidermal Keratinocyte Differentiation
The Journal of investigative dermatology, 2018Co-Authors: Haruyo Yamanishi, Tsutomu Soma, Jiro Kishimoto, Toshihiko Hibino, Akemi Ishida-yamamotoAbstract:Epidermal Lamellar Granules transport various lipids, proteins, and protein inhibitors from the trans-Golgi network to the extracellular space, and play an important role in skin barrier formation. We elucidated the 3-dimensional structure of Lamellar Granules and the trans-Golgi network in normal human skin by focused ion beam scanning electron microscopy. Reconstructed focused ion beam scanning electron microscopy 3-dimensional images revealed that the overall Lamellar Granule structure changed from vesicular to reticular within the second layer of the stratum granulosum. Furthermore, the trans-Golgi network was well developed within this layer and spread through the cytoplasm with branched, tubular structures that connected to Lamellar Granules. Our study reveals the unique overall 3-dimensional structure of Lamellar Granules and the trans-Golgi network within the cells of the epidermis, and provides the basis for an understanding of the skin barrier formation.
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Lamellar Granule Secretion Starts before the Establishment of Tight Junction Barrier for Paracellular Tracers in Mammalian Epidermis
PloS one, 2012Co-Authors: Akemi Ishida-yamamoto, Mari Kishibe, Hidetoshi Takahashi, Masamoto Murakami, Masaru Honma, Hajime IizukaAbstract:Defects in epidermal barrier function and/or vesicular transport underlie severe skin diseases including ichthyosis and atopic dermatitis. Tight junctions (TJs) form a single layered network in simple epithelia. TJs are important for both barrier functions and vesicular transport. Epidermis is stratified epithelia and Lamellar Granules (LGs) are secreted from the stratum granulosum (SG) in a sequential manner. Previously, continuous TJs and paracellular permeability barriers were found in the second layer (SG2) of SG in mice, but their fate and correlation with LG secretion have been poorly understood. We studied epidermal TJ-related structures in humans and in mice and found occludin/ZO-1 immunoreactive multilayered networks spanning the first layer of SG (SG1) and SG2. Paracellular penetration tracer passed through some TJs in SG2, but not in SG1. LG secretion into the paracellular tracer positive spaces started below the level of TJs of SG1. Our study suggests that LG-secretion starts before the establishment of TJ barrier in the mammalian epidermis.
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Involvement of corneodesmosome degradation and Lamellar Granule transportation in the desquamation process
Medical Molecular Morphology, 2011Co-Authors: Akemi Ishida-yamamoto, Mari KishibeAbstract:Desquamation in the mammalian skin is a well-balanced process of producing corneocytes and shedding them from the surface of the skin. The corneodesmosome, which is a modified desmosome, is the main adhesive structure in the cornified cell layer. The major extracellular constituents of corneodesmosomes are desmoglein 1, desmocollin 1, and corneodesmosin. Proteases involved in the degradation of corneodesmosomes and their inhibitors are secreted from Lamellar Granules in the granular cell layer. Genetic defects in corneodesmosin and protease inhibitors result in accelerated desquamation and severe barrier impairment. Abnormalities in transportation and secretion of Lamellar Granules underlie ichthyosis seen in certain human diseases.
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Defective Lamellar Granule Secretion in Arthrogryposis, Renal Dysfunction, and Cholestasis Syndrome Caused by a Mutation in VPS33B
Archives of dermatology, 2008Co-Authors: Dov Hershkovitz, Akemi Ishida-yamamoto, Hannah Mandel, Ilana Chefetz, Bayan Hino, Anthony Luder, Margarita Indelman, Reuven Bergman, Eli SprecherAbstract:Background Arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome is a rare and usually fatal metabolic autosomal recessive disorder, which has recently been shown to result from mutations in VPS33B located on chromosome 15q26.1. Neurological signs and ichthyosis almost invariably accompany the disease. Observations We assessed a consanguineous family with 2 identical twins affected with ARC syndrome. Complete sequencing of the VPS33B gene revealed a homozygous missense mutation (D234H), which segregated with the disease in the affected family. The mutation causes aberrant splicing, resulting in the skipping of exon 9 or exons 9 and 10. VPS33B encodes a homologue of the class C yeast vacuolar protein-sorting molecule, Vps33, which regulates soluble N -ethylmaleimide–sensitive factor attachment protein receptor (SNARE) protein–mediated vesicle-to-target fusion, necessary for secretion to occur. Lamellar Granules, forming a specialized vesicular system in the epidermal upper layers, are usually secreted at the boundary between granular and lower cornified cell layers. However, ultrastructural examination of the skin in ARC syndrome revealed many entombed Lamellar Granules in the cornified cells. Conclusions The present observations indicate that VPS33B deficiency results in abnormal secretion of Lamellar Granules, which underlies ichthyosis in ARC syndrome. These data underscore the importance of SNARE-mediated vesicle fusion during normal epidermal differentiation.
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Eccrine syringofibroadenoma (Mascaro). An ultrastructural and immunohistochemical study.
The American Journal of dermatopathology, 1996Co-Authors: Akemi Ishida-yamamoto, Hajime IizukaAbstract:Eccrine syringofibroadenoma is a rare benign skin tumor, which usually develops on the extremities of elderly persons. We performed immunohistochemical and ultrastructural studies of a typical case of eccrine syringofibroadenoma that developed on the left heel of a 58-year-old man. The tumor consisted of anastomosing thin epithelial strands connected to the epidermis. There were many ductal or cystic structures, and their luminal cells were strongly positive to antibodies against carcinoembryonic antigen and epithelial membrane antigen. Filagrin and involucrin immunoreactivities were also detected in some cells surrounding the ducts. Keratins K1 and K10, co-expressed in the peripheral cells of normal acrosyringia, were colocalized in small cell clusters. Ultrastructurally, intracellular duct formation characteristic of developing acrosyringia was observed. Tumor cells containing globular keratohyaline Granules with various electron densities were seen around some ductal structures. In these areas, keratinization took place without Lamellar Granule formation or prominent cornified cell envelope assembly. These results suggest acrosyringial differentiation of this tumor.
Hidetoshi Takahashi - One of the best experts on this subject based on the ideXlab platform.
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Lamellar Granule Secretion Starts before the Establishment of Tight Junction Barrier for Paracellular Tracers in Mammalian Epidermis
PloS one, 2012Co-Authors: Akemi Ishida-yamamoto, Mari Kishibe, Hidetoshi Takahashi, Masamoto Murakami, Masaru Honma, Hajime IizukaAbstract:Defects in epidermal barrier function and/or vesicular transport underlie severe skin diseases including ichthyosis and atopic dermatitis. Tight junctions (TJs) form a single layered network in simple epithelia. TJs are important for both barrier functions and vesicular transport. Epidermis is stratified epithelia and Lamellar Granules (LGs) are secreted from the stratum granulosum (SG) in a sequential manner. Previously, continuous TJs and paracellular permeability barriers were found in the second layer (SG2) of SG in mice, but their fate and correlation with LG secretion have been poorly understood. We studied epidermal TJ-related structures in humans and in mice and found occludin/ZO-1 immunoreactive multilayered networks spanning the first layer of SG (SG1) and SG2. Paracellular penetration tracer passed through some TJs in SG2, but not in SG1. LG secretion into the paracellular tracer positive spaces started below the level of TJs of SG1. Our study suggests that LG-secretion starts before the establishment of TJ barrier in the mammalian epidermis.
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LEKTI is localized in Lamellar Granules, separated from KLK5 and KLK7, and is secreted in the extracellular spaces of the superficial stratum granulosum.
The Journal of investigative dermatology, 2005Co-Authors: Céline Deraison, Chrystelle Bonnart, R A Robinson, Emmanuelle Bitoun, Timothy O'brien, Kotaro Wakamatsu, Sawa Ohtsubo, Hidetoshi Takahashi, Yoshio HashimotoAbstract:Lympho-epithelial Kazal-type-related inhibitor (LEKTI) is a putative serine protease inhibitor encoded by serine protease inhibitor Kazal-type 5 (SPINK5). It is strongly expressed in differentiated keratinocytes in normal skin but expression is markedly reduced or absent in Netherton syndrome (NS), a severe ichthyosis caused by SPINK5 mutations. At present, however, both the precise intracellular localization and biological roles of LEKTI are not known. To understand the functional role of LEKTI, we examined the localization of LEKTI together with kallikrein (KLK)7 and KLK5, possible targets of LEKTI, in the human epidermis, by confocal laser scanning microscopy and immunoelectron microscopy. In normal skin, LEKTI, KLK7, and KLK5 were all found in the Lamellar Granule (LG) system, but were separately localized. LEKTI was expressed earlier than KLK7 and KLK5. In NS skin, LEKTI was absent and an abnormal split in the superficial stratum granulosum was seen in three of four cases. Collectively, these results suggest that in normal skin the LG system transports and secretes LEKTI earlier than KLK7 and KLK5 preventing premature loss of stratum corneum integrity/cohesion. Our data provide new insights into the biological functions of LG and the pathogenesis of NS.
