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Jouni Uitto - One of the best experts on this subject based on the ideXlab platform.
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Type VII Collagen Gene Expression by Cultured Human Cells and in Fetal Skin Abundant mRNA and Protein Levels in Epidermal Keratinocytes
2016Co-Authors: Jaana Ryyninen, Angela M Christiano, S Sollberg, Gabriela M. Parente, Linda C. Chung, Jouni UittoAbstract:Type VII collagen, a genetically distinct member of the colla-gen family, is present in the cutaneous basement membrane zone as an integral component of the Anchoring Fibrils. We have recently isolated several cDNAs that correspond to human type VII collagen sequences. One of these cDNAs (clone K-131) was utilized to examine type VII collagen gene expression in cul-tures of human cells by Northern analyses, in situ hybridiza-tions and indirect immunofluorescence. Northern hybridiza-tions revealed the presence ofan- 9-kbmRNA transcript, and indicated a high level of expression in epidermal keratinocytes as well as in an oral epidermoid carcinoma cell line (KB), while the expression was considerably lower in skin fibroblasts and in several virally or spontaneously transformed epithelial cell lines. In situ hybridizations of cultured keratinocytes supported the notion of a high level of gene expression. Indirect immuno-fluorescence of skin from a 19-wk fetus revealed type VII colla-gen gene expression at the dermal-epidermal basement mem-brane zone. These results indicate that several different cell types including epidermal keratinocytes and dermal fibroblasts express the type VII collagen gene, but epidermal keratino-cytes may be the primary cell source of type VII collagen in developing human skin. (J. Clin. Invest. 1992. 89:163-168.) Key words: cutaneous basement membrane zone * Anchoring Fibrils * dystrophic epidermolysis bullos
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type vii collagen the Anchoring fibril protein at fault in dystrophic epidermolysis bullosa
Dermatologic Clinics, 2010Co-Authors: Hye Jin Chung, Jouni UittoAbstract:: Type VII collagen is a major component of the Anchoring Fibrils of the dermal-epidermal adhesion on the dermal side at the lamina densa/papillary dermis interface. Dystrophic epidermolysis bullosa (DEB) emerged as a candidate for type VII collagen mutations becausing Anchoring Fibrils were shown to be morphologically altered, reduced in number, or completely absent in patients with different forms of DEB. Circulating autoantibodies recognize type VII collagen epitopes in epidermolysis bullosa acquisita. The suggestion that type VII collagen is required for human epidermal tumorigenesis relates to the increasing numbers of life-threatening complications associated with developing squamous cell carcinomas because of the extended life span of affected individuals with recessive DEB.
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amelioration of epidermolysis bullosa by transfer of wild type bone marrow cells
Blood, 2009Co-Authors: Jakub Tolar, Jouni Uitto, Angela M Christiano, Akemi Ishidayamamoto, Megan J Riddle, Ron T Mcelmurry, Mark J Osborn, Troy C Lund, Catherine Slattery, John E WagnerAbstract:The recessive dystrophic form of epidermolysis bullosa (RDEB) is a disorder of incurable skin fragility and blistering caused by mutations in the type VII collagen gene (Col7a1). The absence of type VII collagen production leads to the loss of adhesion at the basement membrane zone due to the absence of Anchoring Fibrils, which are composed of type VII collagen. We report that wild-type, congenic bone marrow cells homed to damaged skin, produced type VII collagen protein and Anchoring Fibrils, ameliorated skin fragility, and reduced lethality in the murine model of RDEB generated by targeted Col7a1 disruption. These data provide the first evidence that a population of marrow cells can correct the basement membrane zone defect found in mice with RDEB and offer a potentially valuable approach for treatment of human RDEB and other extracellular matrix disorders.
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Single Amino Acid Substitutions in Procollagen VII Affect Early Stages of Assembly of Anchoring Fibrils
Journal of Biological Chemistry, 2004Co-Authors: Raymond Brittingham, Morgana Colombo, Andrzej Steplewski, David E Birk, Jouni Uitto, Andrzej FertalaAbstract:Abstract Procollagen VII is a homotrimer of 350-kDa pro-α1(VII) chains, each consisting of a central collagenous domain flanked by the noncollagenous N-terminal NC1 domain and the C-terminal NC2 domain. After secretion from cells, procollagen VII molecules form anti-parallel dimers with a C-terminal 60-nm overlap. Characteristic alignment of procollagen VII monomers forming a dimer depends on site-specific binding between the NC2 domain and the triple-helical region adjacent to Cys-2634 of the interacting procollagen VII molecules. Formation of the intermolecular disulfide bonds between Cys-2634 and either Cys-2802 or Cys-2804 is promoted by the cleavage of the NC2 domain by procollagen C-proteinase. By employing recombinant procollagen VII variants harboring G2575R, R2622Q, or G2623C substitutions previously disclosed in patients with dystrophic epidermolysis bullosa, we studied how these amino acid substitutions affect intermolecular interactions. Binding assays utilizing an optical biosensor demonstrated that the G2575R substitution increased affinity between mutant molecules. In contrast, homotypic binding between the R2622Q or G2623C molecules was not detected. In addition, kinetics of heterotypic binding of all analyzed mutants to wild type collagen VII were different from those for binding between wild type molecules. Moreover, solid-state binding assays demonstrated that R2622Q and G2623C substitutions prevent formation of stable assemblies of procollagen C-proteinase-processed mutants. These results indicate that single amino acid substitutions in procollagen VII alter its self-assembly and provide a basis for understanding the pathomechanisms leading from mutations in the COL7A1 gene to fragility of the dermal-epidermal junction seen in patients with dystrophic forms of epidermolysis bullosa.
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genetic basis of dominantly inherited transient bullous dermolysis of the newborn a splice site mutation in the type vii collagen gene
Journal of Investigative Dermatology, 1997Co-Authors: Angela M Christiano, Jodavid Fine, Jouni UittoAbstract:Transient bullous dermolysis of the newborn (TBDN) is a blistering disease evident at birth or shortly thereafter, but the blistering tendency decreases with advancing age. The tissue separation in TBDN is below the lamina densa, and electron microscopy has revealed abnormalities in Anchoring Fibrils. Immunofluorescence staining demonstrates intracellular accumulation of type VII collagen. In this study, we report a G-to-C transversion mutation in the last nucleotide of intron 35 of the type VII collagen gene (COL7A1) in a family with autosomal dominant TBDN in three generations. This nucleotide substitution abolishes the obligatory consensus 3'-acceptor splice site, predicting in-frame skipping of exon 36. Thus, TBDN in this family is caused by a mutation in COL7A1, and is therefore allelic with other variants of dominant dystrophic epidermolysis bullosa.
Leena Brucknertuderman - One of the best experts on this subject based on the ideXlab platform.
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supramolecular interactions in the dermo epidermal junction zone Anchoring fibril collagen vii tightly binds to banded collagen Fibrils
Journal of Biological Chemistry, 2008Co-Authors: Daniela Villone, Leena Brucknertuderman, Manuel Koch, Anja Fritsch, Uwe Hansen, Peter BrucknerAbstract:The dermis and the epidermis of normal human skin are functionally separated by a basement membrane but, together, form a stable structural continuum. Anchoring Fibrils reinforce this connection by insertion into the basement membrane and by intercalation with banded collagen Fibrils of the papillary dermis. Structural abnormalities in collagen VII, the major molecular constituent of Anchoring Fibrils, lead to a congenital skin fragility condition, dystrophic epidermolysis bullosa, associated with skin blistering. Here, we characterized the molecular basis of the interactions between Anchoring Fibrils and banded collagen Fibrils. Suprastructural fragments of the dermo-epidermal junction zone were generated by mechanical disruption and by separation with magnetic Immunobeads. Anchoring Fibrils were tightly attached to banded collagen Fibrils. In vitro binding studies demonstrated that a von Willebrand factor A-like motif in collagen VII was essential for binding of Anchoring Fibrils to reconstituted collagen I Fibrils. Since collagen I and VII molecules reportedly undergo only weak interactions, the attachment of Anchoring Fibrils to collagen Fibrils depends on supramolecular organization of their constituents. This complex is stabilized in situ and resists dissociation by strong denaturants.
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immunomapping of eba sera to multiple epitopes on collagen vii further evidence that Anchoring Fibrils originate and terminate in the lamina densa
Experimental Dermatology, 2003Co-Authors: James R Mcmillan, Leena Brucknertuderman, Takashi Hashimoto, Tetsuri Matsumura, Hans Schumann, Hiroshi ShimizuAbstract:Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering disease with circulating antibodies to type VII collagen, a major component of Anchoring Fibrils located at the dermal-epidermal junction. The purpose of this study was to further confirm the ultrastructural organisation of Anchoring Fibrils and to assess the relationship between the clinical phenotype of EBA and target site of their autoantibodies on Anchoring Fibrils. We studied the ultrastructural binding site of circulating autoantibodies from two patients with atypical clinical features who predominantly presented with oral lesions, and compared this with two patients with clinically typical forms of EBA. Immunoblotting of whole dermal extracts showed labelling of 290-kDa bands consistent with that of type VII collagen as well as the non-collagenous (NC-1) domain fusion protein in three out of four patients' sera. Postembedding immunoelectron microscopy (IEM) using Lowicryl K11M embedded normal human skin and patients' sera demonstrated the majority of labelling within the lamina densa, not below the lamina densa. We conclude that EBA autoantibodies in these patient's sera bind to the NC-1 domain of collagen VII situated in the lamina densa of the epidermal basement membrane, regardless of the EBA clinical phenotype. This confirms the previous notion that Anchoring Fibrils originate and terminate in the lamina densa.
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hereditary skin diseases of Anchoring Fibrils
Journal of Dermatological Science, 1999Co-Authors: Leena BrucknertudermanAbstract:Abstract Remarkable progress has been made in the last few years in understanding the functions of the Anchoring Fibrils, polymers of collagen VII, that connect the epidermal basement membrane with the dermal connective tissue. Novel insights into the biology of these Fibrils have been gained from studies on dystrophic epidermolysis bullosa (DEB), a group of inherited blistering disorders caused by abnormalities of the Anchoring Fibrils. Mutations in the COL7A1 gene encoding collagen VII have been disclosed in a number of DEB families, and the mutation analyses and studies on genotype–phenotype correlations in DEB have revealed an unusual complexity of the gene defects and their biological consequences. In analogy to heritable disorders of other collagen genes, predictable phenotypes of COL7A1 mutations causing premature termination codons (PTC) or dominant negative interference have been observed. However, collagen VII seems to be unique among collagens in that many mutations lead to minimal phenotypes, or to no phenotype at all. Furthermore, the mild DEB phenotypes can be severely modulated by a second mutation in individuals compound heterozygous for two different COL7A1 defects. Therefore, not only definition of mutations with diagnostic analyses, but also cell biological, protein chemical and suprastructural studies of the mutated molecules are required for understanding the pathomechanisms underlying DEB.
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biology of Anchoring Fibrils lessons from dystrophic epidermolysis bullosa
Matrix Biology, 1999Co-Authors: Leena Brucknertuderman, Bianca Hopfner, Nadja HammamihauasliAbstract:Anchoring Fibrils are adhesive suprastructures that ensure the connection of the epidermal basement membrane with the dermal extracellular matrix. The Fibrils represent polymers of collagen VII, the major structural fibril component, but may also contain other proteins. Remarkable progress has been made in the last few years in understanding the functions of skin basement membrane components including the Anchoring Fibrils. Novel insights into the biology of the Anchoring Fibrils have been gained from experimental studies on dystrophic epidermolysis bullosa (DEB), a group of inherited blistering disorders caused by mutations in the gene for collagen VII, COL7A1. Mutation analyses of DEB families have disclosed more than 100 COL7A1 gene defects so far, but the unusual complexity of the mutation constellations and their biological consequences are only beginning to emerge. In analogy to heritable disorders of other collagen genes, predictable phenotypes of COL7A1 mutations causing premature termination codons or dominant negative interference have been observed. However, collagen VII seems to represent a remarkable exception among collagens in that many mutations, including heterozygous glycine substitutions and deletions, lead to minimal phenotypes, or to no phenotype at all. In contrast to fibrillar collagens, structural abnormalities of collagen VII molecules in Anchoring Fibrils appear to be tolerated to a certain extent. However, the mild DEB phenotypes can be severely modulated by a second aberration in individuals compound heterozygous for two different COL7A1 mutations. Therefore, not only definition of mutation(s) but also cell biological, protein chemical and suprastructural studies of the mutated molecules yield novel insight into the molecular pathomechanisms underlying disease.
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some but not all glycine substitution mutations in col7a1 result in intracellular accumulation of collagen vii loss of Anchoring Fibrils and skin blistering
Journal of Biological Chemistry, 1998Co-Authors: Nadja Hammamihauasli, Hauke Schumann, Oliver Kilgus, Ursula Luthi, Michael Raghunath, Thomas A. Luger, Leena BrucknertudermanAbstract:COL7A1 gene mutations cause dystrophic epidermolysis bullosa, a skin blistering disorder. The phenotypes result from defects of collagen VII, the major component of the Anchoring Fibrils at the dermo-epidermal junction; however, the molecular mechanisms underlying the phenotypes remain elusive. We investigated naturally occurring COL7A1 mutations and showed that some, but not all, glycine substitutions in collagen VII interfered with biosynthesis of the protein in a dominant-negative manner. Three point mutations in exon 73 caused glycine substitutions G2006D, G2034R, and G2015E in the triple helical domain of collagen VII and interfered with its folding and secretion. Confocal laser scanning studies and semiquantitative immunoblotting determined that dystrophic epidermolysis bullosa keratinocytes retained up to 2.5-fold more procollagen VII within the rough endoplasmic reticulum than controls. Limited proteolytic digestions of mutant procollagen VII produced aberrant fragments and revealed reduced stability of the triple helix. In contrast, the glycine substitution G1519D in another segment of the triple helix affected neither procollagen VII secretion nor Anchoring fibril function and remained phenotypically silent. These data demonstrate that collagen VII presents a remarkable exception among collagens in that not all glycine substitutions within the triple helix exert dominant-negative interference and that the biological consequences of the substitutions probably depend on their position within the triple helix.
David T Woodley - One of the best experts on this subject based on the ideXlab platform.
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de novo anti type vii collagen antibodies in patients with recessive dystrophic epidermolysis bullosa
Journal of Investigative Dermatology, 2014Co-Authors: David T Woodley, Douglas R Keene, Jon Cogan, Xinyi Wang, Cyrus Haghighian, Gail Kudo, Mei ChenAbstract:The two main layers of human skin are held together by structures at the dermal-epidermal junction (DEJ) called Anchoring Fibrils (AFs). Without properly functioning AFs, the adherence between the epidermis and dermis is compromised. Clinically, this translates into skin fragility and skin bullae. AFs are composed of type VII collagen (C7) that has a central triple helical domain (TH) flanked by a 145-kDa non-collagenous amino-terminal domain (NC1) and a 30-kDa carboxyl-terminal domain (NC2) (Burgeson et al., 1993). AFs and C7 are perturbed in recessive dystrophic epidermolysis bullosa (RDEB), a disease characterized clinically by skin fragility, skin bullae, scarring, and nail loss (Fine et al., 2008). RDEB is caused by mutations in the COL7A1 gene encoding C7. Over 700 mutations have been identified in DEB patients (Wertheim -Tysarowska et al., 2012). According to a recent consensus report, RDEB is classified as RDEB, severe, generalized (RDEB-sev, gen), RDEB, generalized, other (RDEB-O) and RDEB inversa (RDEB-I) (Fine et al., 2008).
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epidermolysis bullosa acquisita
The New England Journal of Medicine, 2013Co-Authors: Mei Chen, Dafna Hallelhalevy, David T WoodleyAbstract:EBA is a clinically heterogeneous acquired, subepidermal bullous disease. In its classical form, it is a mechanobullous disease with skin fragility and trauma-induced blisters that have minimal inflammation and heal with scarring and milia — features that are highly reminiscent of hereditary dystrophic forms of epidermolysis bullosa. A hallmark of EBA are IgG autoantibodies targeted against the type VII collagen within Anchoring Fibrils. Anchoring Fibrils are structures that anchor the epidermis and its underlying BMZ onto the dermis. However, it has also become evident that EBA may present with clinical manifestations reminiscent of bullous pemphigoid (BP), cicatricial pemphigoid (CP), and Brunsting-Perry pemphigoid. The diagnostic criteria for EBA are: (1) spontaneous or trauma-induced blisters resembling hereditary DEB, (2) adult onset, (3) a negative family history for EB, and (4) the exclusion of all other bullous diseases. Due to the pronounced skin fragility caused by the autoantibody-induced paucity of Anchoring Fibrils, EBA is difficult to treat. The BP-like inflammatory variants of EBA respond well to systemic corticosteroids and immunosuppressive adjuvants while the mechanobullous variant and the MMP-like variants do to a much lesser extent. Novel therapeutic strategies such as immunoadsorption and the anti-CD20 monoclonal antibody, rituximab, had beneficial effects in small case series.
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epidermolysis bullosa acquisita autoimmunity to Anchoring fibril collagen
Autoimmunity, 2012Co-Authors: Mei Chen, Lori Prakash, David T WoodleyAbstract:Epidermolysis bullosa acquisita (EBA) is a rare and acquired autoimmune subepidermal bullous disease of skin and mucosa. EBA includes various distinct clinical manifestations resembling genetic dystrophic epidermolysis bullosa (DEB), Bullous pemphigus, Brunsting–Perry pemphigoid, or cicatricial pemphigoid. These patients have autoantibodies against type VII collagen (C7), an integral component of Anchoring Fibrils (AFs), which are responsible for attaching the dermis to the epidermis. Destruction or perturbation of the normal functioning AFs clinically results in skin fragility, blisters, erosions, scars, milia, and nail loss, all features reminiscent of genetic dystrophic epidermolysis bullosa. These anti-C7 antibodies are “pathogenic” because when injected into a mouse, the mouse develops an EBA-like blistering disease. Currently, treatment is often unsatisfactory; however, some success has been achieved with colchicine, dapsone, photopheresis, plasmapheresis, infliximab, rituximab, and IVIG.
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epidermolysis bullosa acquisita
Clinics in Dermatology, 2012Co-Authors: Rishu Gupta, David T Woodley, Mei ChenAbstract:Abstract Epidermolysis bullosa acquisita (EBA) is a rare, acquired, chronic subepidermal bullous disease of the skin and mucosa characterized by autoantibodies to type VII collagen (C7) structures, a major component of Anchoring Fibrils, which attach the epidermis to the dermis. EBA patients have tissue-bound and circulating antitype C7 autoantibodies that attack type C7 and result in a reduction or perturbation of normally functioning Anchoring Fibrils. Patients with EBA have skin fragility, blisters, erosions, scars, milia, and nail loss, all features reminiscent of genetic dystrophic epidermolysis bullosa. These immunoglobulin G antitype C7 antibodies are pathogenic, because when they are injected into mice, the mice develop an EBA-like blistering disease. In addition to the classical mechanobullous presentation, EBA also has several other distinct clinical syndromes similar to bullous pemphigoid, Brunsting-Perry pemphigoid, or cicatricial pemphigoid. Although treatment for EBA is often unsatisfactory, some therapeutic success has been achieved with colchicine, dapsone, plasmapheresis, photopheresis, infliximab, and intravenous immunoglobulin.
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bone marrow transplantation for recessive dystrophic epidermolysis bullosa
The New England Journal of Medicine, 2010Co-Authors: John E Wagner, David T Woodley, Mei Chen, Douglas R Keene, Akemi Ishidayamamoto, Megan J Riddle, Mark J Osborn, John A Mcgrath, Maria K Hordinsky, Troy C LundAbstract:Background Recessive dystrophic epidermolysis bullosa is an incurable, often fatal mucocutaneous blistering disease caused by mutations in COL7A1, the gene encoding type VII collagen (C7). On the basis of preclinical data showing biochemical correction and prolonged survival in col7 −/− mice, we hypothesized that allogeneic marrow contains stem cells capable of ameliorating the manifestations of recessive dystrophic epidermolysis bullosa in humans. Methods Between October 2007 and August 2009, we treated seven children who had recessive dystrophic epidermolysis bullosa with immunomyeloablative chemotherapy and allogeneic stem-cell transplantation. We assessed C7 expression by means of immunofluorescence staining and used transmission electron microscopy to visualize Anchoring Fibrils. We measured chimerism by means of competitive polymerase-chain-reaction assay, and documented blister formation and wound healing with the use of digital photography. Results One patient died of cardiomyopathy before transpl...
Mei Chen - One of the best experts on this subject based on the ideXlab platform.
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de novo anti type vii collagen antibodies in patients with recessive dystrophic epidermolysis bullosa
Journal of Investigative Dermatology, 2014Co-Authors: David T Woodley, Douglas R Keene, Jon Cogan, Xinyi Wang, Cyrus Haghighian, Gail Kudo, Mei ChenAbstract:The two main layers of human skin are held together by structures at the dermal-epidermal junction (DEJ) called Anchoring Fibrils (AFs). Without properly functioning AFs, the adherence between the epidermis and dermis is compromised. Clinically, this translates into skin fragility and skin bullae. AFs are composed of type VII collagen (C7) that has a central triple helical domain (TH) flanked by a 145-kDa non-collagenous amino-terminal domain (NC1) and a 30-kDa carboxyl-terminal domain (NC2) (Burgeson et al., 1993). AFs and C7 are perturbed in recessive dystrophic epidermolysis bullosa (RDEB), a disease characterized clinically by skin fragility, skin bullae, scarring, and nail loss (Fine et al., 2008). RDEB is caused by mutations in the COL7A1 gene encoding C7. Over 700 mutations have been identified in DEB patients (Wertheim -Tysarowska et al., 2012). According to a recent consensus report, RDEB is classified as RDEB, severe, generalized (RDEB-sev, gen), RDEB, generalized, other (RDEB-O) and RDEB inversa (RDEB-I) (Fine et al., 2008).
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epidermolysis bullosa acquisita
The New England Journal of Medicine, 2013Co-Authors: Mei Chen, Dafna Hallelhalevy, David T WoodleyAbstract:EBA is a clinically heterogeneous acquired, subepidermal bullous disease. In its classical form, it is a mechanobullous disease with skin fragility and trauma-induced blisters that have minimal inflammation and heal with scarring and milia — features that are highly reminiscent of hereditary dystrophic forms of epidermolysis bullosa. A hallmark of EBA are IgG autoantibodies targeted against the type VII collagen within Anchoring Fibrils. Anchoring Fibrils are structures that anchor the epidermis and its underlying BMZ onto the dermis. However, it has also become evident that EBA may present with clinical manifestations reminiscent of bullous pemphigoid (BP), cicatricial pemphigoid (CP), and Brunsting-Perry pemphigoid. The diagnostic criteria for EBA are: (1) spontaneous or trauma-induced blisters resembling hereditary DEB, (2) adult onset, (3) a negative family history for EB, and (4) the exclusion of all other bullous diseases. Due to the pronounced skin fragility caused by the autoantibody-induced paucity of Anchoring Fibrils, EBA is difficult to treat. The BP-like inflammatory variants of EBA respond well to systemic corticosteroids and immunosuppressive adjuvants while the mechanobullous variant and the MMP-like variants do to a much lesser extent. Novel therapeutic strategies such as immunoadsorption and the anti-CD20 monoclonal antibody, rituximab, had beneficial effects in small case series.
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epidermolysis bullosa acquisita autoimmunity to Anchoring fibril collagen
Autoimmunity, 2012Co-Authors: Mei Chen, Lori Prakash, David T WoodleyAbstract:Epidermolysis bullosa acquisita (EBA) is a rare and acquired autoimmune subepidermal bullous disease of skin and mucosa. EBA includes various distinct clinical manifestations resembling genetic dystrophic epidermolysis bullosa (DEB), Bullous pemphigus, Brunsting–Perry pemphigoid, or cicatricial pemphigoid. These patients have autoantibodies against type VII collagen (C7), an integral component of Anchoring Fibrils (AFs), which are responsible for attaching the dermis to the epidermis. Destruction or perturbation of the normal functioning AFs clinically results in skin fragility, blisters, erosions, scars, milia, and nail loss, all features reminiscent of genetic dystrophic epidermolysis bullosa. These anti-C7 antibodies are “pathogenic” because when injected into a mouse, the mouse develops an EBA-like blistering disease. Currently, treatment is often unsatisfactory; however, some success has been achieved with colchicine, dapsone, photopheresis, plasmapheresis, infliximab, rituximab, and IVIG.
-
epidermolysis bullosa acquisita
Clinics in Dermatology, 2012Co-Authors: Rishu Gupta, David T Woodley, Mei ChenAbstract:Abstract Epidermolysis bullosa acquisita (EBA) is a rare, acquired, chronic subepidermal bullous disease of the skin and mucosa characterized by autoantibodies to type VII collagen (C7) structures, a major component of Anchoring Fibrils, which attach the epidermis to the dermis. EBA patients have tissue-bound and circulating antitype C7 autoantibodies that attack type C7 and result in a reduction or perturbation of normally functioning Anchoring Fibrils. Patients with EBA have skin fragility, blisters, erosions, scars, milia, and nail loss, all features reminiscent of genetic dystrophic epidermolysis bullosa. These immunoglobulin G antitype C7 antibodies are pathogenic, because when they are injected into mice, the mice develop an EBA-like blistering disease. In addition to the classical mechanobullous presentation, EBA also has several other distinct clinical syndromes similar to bullous pemphigoid, Brunsting-Perry pemphigoid, or cicatricial pemphigoid. Although treatment for EBA is often unsatisfactory, some therapeutic success has been achieved with colchicine, dapsone, plasmapheresis, photopheresis, infliximab, and intravenous immunoglobulin.
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bone marrow transplantation for recessive dystrophic epidermolysis bullosa
The New England Journal of Medicine, 2010Co-Authors: John E Wagner, David T Woodley, Mei Chen, Douglas R Keene, Akemi Ishidayamamoto, Megan J Riddle, Mark J Osborn, John A Mcgrath, Maria K Hordinsky, Troy C LundAbstract:Background Recessive dystrophic epidermolysis bullosa is an incurable, often fatal mucocutaneous blistering disease caused by mutations in COL7A1, the gene encoding type VII collagen (C7). On the basis of preclinical data showing biochemical correction and prolonged survival in col7 −/− mice, we hypothesized that allogeneic marrow contains stem cells capable of ameliorating the manifestations of recessive dystrophic epidermolysis bullosa in humans. Methods Between October 2007 and August 2009, we treated seven children who had recessive dystrophic epidermolysis bullosa with immunomyeloablative chemotherapy and allogeneic stem-cell transplantation. We assessed C7 expression by means of immunofluorescence staining and used transmission electron microscopy to visualize Anchoring Fibrils. We measured chimerism by means of competitive polymerase-chain-reaction assay, and documented blister formation and wound healing with the use of digital photography. Results One patient died of cardiomyopathy before transpl...
Hassan Vahidnezhad - One of the best experts on this subject based on the ideXlab platform.
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mutations in plod3 encoding lysyl hydroxylase 3 cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa like blistering phenotype with abnormal Anchoring Fibrils and type vii collagen deficiency
Matrix Biology, 2019Co-Authors: Hassan Vahidnezhad, Leila Youssefian, Amir Hossein Saeidian, Andrew Touati, Sara Pajouhanfar, Taghi Baghdadi, Azam Ahmadi ShadmehriAbstract:Abstract Epidermolysis bullosa (EB), the paradigm of heritable skin fragility disorders, is associated with mutations in as many as 20 distinct genes. One of the clinical variants, recessive dystrophic EB (RDEB), demonstrates sub-lamina densa blistering accompanied by alterations in Anchoring Fibrils due to mutations in COL7A1. In this study, we characterized a patient with widespread connective tissue abnormalities, including skin blistering similar to that in RDEB. Whole exome sequencing, combined with genome-wide homozygosity mapping, identified a homozygous missense mutation in PLOD3 encoding lysyl hydroxylase 3 (LH3). No mutations in COL7A1, the gene previously associated with RDEB, were detected. The level of LH3 was dramatically reduced in the skin and fibroblast cultures from the patient. The blistering in the skin occurred below the lamina densa and was associated with variable density and morphology of Anchoring Fibrils. The level of type VII collagen expression in the skin was markedly reduced. Analysis of hydroxylysine and its glycosylated derivatives (galactosyl-hydroxylysine and glucosyl-galactosyl-hydroxylysine) revealed marked reduction in glycosylated hydroxylysine. Collectively, these findings indicate that PLOD3 mutations can result in a dystrophic EB-like phenotype in the spectrum of connective tissue disorders and add it to the list of candidate genes associated with skin fragility.
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mutations in plod3 encoding lysyl hydroxylase 3 cause a complex connective tissue disorder including recessive dystrophic epidermolysis bullosa like blistering phenotype with abnormal Anchoring Fibrils and type vii collagen deficiency
Matrix Biology, 2019Co-Authors: Hassan Vahidnezhad, Leila Youssefian, Amir Hossein Saeidian, Andrew Touati, Sara Pajouhanfar, Taghi Baghdadi, Azam Ahmadi Shadmehri, Cecilia Giunta, Marius E Kraenzlin, Delfien SyxAbstract:Epidermolysis bullosa (EB), the paradigm of heritable skin fragility disorders, is associated with mutations in as many as 20 distinct genes. One of the clinical variants, recessive dystrophic EB (RDEB), demonstrates sub-lamina densa blistering accompanied by alterations in Anchoring Fibrils due to mutations in COL7A1. In this study, we characterized a patient with widespread connective tissue abnormalities, including skin blistering similar to that in RDEB. Whole exome sequencing, combined with genome-wide homozygosity mapping, identified a homozygous missense mutation in PLOD3 encoding lysyl hydroxylase 3 (LH3). No mutations in COL7A1, the gene previously associated with RDEB, were detected. The level of LH3 was dramatically reduced in the skin and fibroblast cultures from the patient. The blistering in the skin occurred below the lamina densa and was associated with variable density and morphology of Anchoring Fibrils. The level of type VII collagen expression in the skin was markedly reduced. Analysis of hydroxylysine and its glycosylated derivatives (galactosyl-hydroxylysine and glucosyl-galactosyl-hydroxylysine) revealed marked reduction in glycosylated hydroxylysine. Collectively, these findings indicate that PLOD3 mutations can result in a dystrophic EB-like phenotype in the spectrum of connective tissue disorders and add it to the list of candidate genes associated with skin fragility.