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PubMed2000

Glycine substitution mutations by different amino acids in the same codon of COL7A1 lead to heterogeneous clinical phenotypes of dominant dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa (DEB), caused by mutations in the gene encoding type VII collagen (COL7A1), is known to show heterogeneous clinical phenotypes. Certain correlations between the nature or position of COL7A1 mutations and the resultant DEB phenotypes have been suggested, although such relationships may be more complex than initially thought. The purpose of the present study was to clarify the molecular basis of two different subtypes of dominant DEB (DDEB), EB pruriginosa and classical type. Interestingly, we found that both cases were caused by a missense glycine substitution mutation by different amino acids in the same codon of COL7A1 (G2028R and G2028A). These results further support the notion that different glycine substitution mutations in the same codon can lead to heterogeneous clinical phenotypes of DDEB, EB pruriginosa and classical type.

Adult↗

PubMed1988

Abnormal binding of lectin to the epidermal cell membranes in the skin of epidermolysis bullosa simplex.

Epidermolysis bullosa (EB) simplex is a congenital disease that has blister formation following minor mechanical trauma to the skin. However, the least amount of information concerning the pathogenesis is known in this condition. One possibility is that there are structural abnormalities in epidermal cell membranes. In the present study, we examined the binding of lectins to epidermal cell membranes by ABC method. Biopsy skin specimens were obtained from patients with simplex, junctional and dystrophic forms of EB, and normal volunteers. In the case of EB simplex, the cell membranes of keratinocytes in the basal and spinous cell layers did not bind to soybean agglutinin in specimens from blister edges or mechanical traumatized areas. No differences were found in binding pattern between the other forms of EB and normal controls. This results suggest the presence of structural abnormalities in epidermis of EB simplex.

Cell Membrane↗

PubMed1997

Epidermolysis bullosa pruriginosa.

Epidermolysis bullosa (EB) pruriginosa is a rare clinical subset of dystrophic EB, characterized by marked itching and presence of prurigo-like or lichenoid features. In order to further delineate the phenotype and understand the pathogenesis of this disorder, the clinical, histological and ultrastructural findings of a 19-year-old patient presenting a typical form of EB pruriginosa are described. The prevalence of papular itchy lichenoid lesions, signs of scratching and paucity of blisters at the time of clinical examination may result in incorrect diagnosis and treatment. Microscopic studies of the lesions show the typical findings of dystrophic EB associated with an unusually high density of collagen bundles and absence of elastic fibres in the upper dermis. Itching lichenoid lesions of EB pruriginosa could represent an abnormal dermal reactivity of some patients to their inherited bullous disorder.

Adult↗

PubMed1993

A missense mutation in the rod domain of keratin 14 associated with recessive epidermolysis bullosa simplex.

Epidermolysis bullosa simplex (EBS) is a group of epidermal blistering diseases almost invariably transmitted as a dominant trait, which has recently been shown to arise from mutations in keratins 14 and 5 (K14 and K5). We describe a family with recessive EBS in which the disease is tightly linked to the substitution of the highly conserved glutamic acid-144 to alanine in the first helical segment of the rod domain of keratin 14. In contrast, linkage with keratin 5 was excluded. The loss of an ionic interaction with keratin 5 is likely to affect K14-K5 heterodimer formation. Our data suggest that this mutation underlies EBS in our family, and that mutations in keratin genes may impair the mechanical integrity of basal keratinocytes in a recessive as well as dominant fashion.

Alanine↗

PubMed2003

A new glycine substitution mutation in the COL7A1 gene in a Chinese family with dominant dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa (DEB) is caused by mutations in the COL7A1 gene encoding type VII collagen, the major component of anchoring fibrils. The characteristic genetic lesion in dominant DEB (DDEB) is a glycine substitution in the collagenous domain of the protein. In this study, we identified a Chinese family with a four-generation pedigree of DDEB, in whom a novel glycine substitution mutation in COL7A1 was demonstrated. A heterozygous nucleotide G-->A transition at position 6208 in exon 74 of COL7A1 was detected, which resulted in a glycine to arginine substitution (G2070R) in the triple-helical domain of type VII collagen. This substitution was not found in 110 unrelated normal alleles. This report emphasizes the predominance of glycine substitution mutations in DDEB and contributes to the expanding database on COL7A1 mutations.

Adolescent↗

PubMed1990

Heavy and light chain isotypes of immunoglobulin in epidermolysis bullosa acquisita.

Epidermolysis bullosa acquisita (EBA) is a chronic acquired blistering disease with characteristic clinical, pathologic, and immunopathologic features. The disease is characterized immunopathologically by circulating and tissue-bound IgG class autoantibodies (EBA antibodies) to the basement membrane zone of stratified squamous epithelium. Previous studies have shown that circulating and tissue-bound EBA antibodies are heterogenous in their ability to activate complement and have raised the possibility that functional heterogeneity might be related to IgG subclass restriction. In this study, we have characterized the IgG subclasses of the circulating and tissue-bound EBA antibodies by immunofluorescence and have examined the relationship between IgG subclass and complement binding. The results show that EBA antibodies belonging to all IgG subclasses are present in the skin of EBA patients. The results also show that EBA antibodies belonging to all IgG subclasses are present in the sera of most patients, including sera with and without complement binding EBA antibodies.

Basement Membrane↗

PubMed2005

Denaturing HPLC-based approach for detection of COL7A1 gene mutations causing dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa (DEB) is a rare clinically heterogeneous genodermatosis due to genetic defects in type VII collagen gene (COL7A1). Identification of COL7A1 mutations is a challenge since this gene comprises 118 exons and more than 300 mutations scattered over the gene have been reported. Here, we describe for the first time the use of denaturing high performance liquid chromatography (DHPLC) for COL7A1 mutation detection. To validate the method, exon-specific DHPLC conditions were applied to screen DNA samples from patients carrying known COL7A1 mutations. Abnormal DHPLC profiles were obtained for all known mutations. Subsequent DHPLC analysis of 17 DEB families of unknown genotype allowed the identification of 21 distinct mutations, 9 of which were novel. The DHPLC mutation detection rate was significantly higher compared with our mutation scanning rate with conventional techniques (97% vs 86%), indicating DHPLC as the method of choice for COL7A1 molecular characterization in DEB patients.

Base Sequence↗

PubMed1990

Cytofluorometric study of lectin binding to the keratinocytes of epidermolysis bullosa simplex.

Epidermolysis bullosa (EB) simplex is a congenital disease that has blister formation following minor mechanical trauma to the skin. The least amount of information concerning the pathogenesis is known in this disease. One possibility is that there are structural abnormalities in keratinocytes. In the present study, we report the binding of lectin (Ricinus communis agglutinin, Peanut agglutinin, and Soybean agglutinin) to keratinocytes using cytofluorometry. Biopsy skin specimens were taken from patients with simplex, junctional, and dystrophic forms of EB, and normal volunteers. Free keratinocytes were obtained by the treatment of EDTA and trypsin, and fractionated by centrifugation on a continuous colloidal silica (Percoll) density gradient. Fractionated basal cells were stained with biotinyl lectins and avidin-FITC, and measured by cytofluorometry. In all lectins examined, the intensity was low in the basal cells of EB simplex, as compared with normal controls. However, there were no differences among the other forms of EB and normal controls. This results suggest the presence of structural abnormalities in epidermis of EB simplex.

Avidin↗

PubMed1994

[Inflammatory type of epidermolysis bullosa acquisita].

Epidermolysis bullosa acquisita (EBA) is an autoimmune subepidermal blistering disease, which can present in various clinical forms. We report on a 73-year-old male patient with the inflammatory type of EBA, which is clinically similar to bullous pemphigoid. Histological examination revealed subepidermal blister formation, and direct immunofluorescence of perilesional skin revealed a linear deposition of IgG and C3 at the basement membrane. Indirect immunofluorescence with 0.9% NaCl-separated human skin as substrate showed the presence of circulating antibodies binding to the base of the artificial blister at a titre of 1:320. Indirect immunoelectronmicroscopy revealed immune deposits localized in the area of the sublamina densa. Immunoblotting of dermal extracts disclosed binding of serum antibodies to a 290-kDa protein. Systemic therapy with diaminodiphenyl sulphone, initially in combination with corticosteroids, resulted in complete healing of the skin lesions. With reference to this case report, we discuss the clinical pictures possible in EBA, the differential diagnosis and the treatment options.

Aged↗

PubMed2002

A novel nonsense mutation at E106 of the 2B rod domain of keratin 14 causes dominant epidermolysis bullosa simplex.

Epidermolysis bullosa simplex (EBS) is classified into three main types and is caused, in most cases, by missense mutations in the genes encoding keratin (K) 5 and K14. In this study, we clinically, ultrastructurally, immunohistochemically, and molecularly studied a patient with a dominant EBS, Köbner type. Using sequence analysis of genomic DNA, a novel K14 nonsense mutation was identified. A heterozygous mutation G1231T of KRT14 was found to be associated with the disease in the patient. The mutation created a premature stop codon (amino acid codon 411, residue 106 of the 2B helix) in the K14 molecule. This residue lies in a highly conserved region and was recently found to be absolutely required for molecular stability and intermediate filament assembly in K5 and K14. The E411X (E106X) heterozygous ablation, missing the last 16 amino acid residues of the 2B and the entire tail domain of K14, led to disease but did not result in clumping of keratin filaments. It is the first premature stop codon mutation of K14 found in dominant EBS.

Adult↗

PubMed2006

Expanding the COL7A1 mutation database: novel and recurrent mutations and unusual genotype-phenotype constellations in 41 patients with dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa (DEB), a heterogeneous hereditary skin disorder characterized by trauma-induced blistering and scarring, affects thousands of families worldwide. The clinical manifestations extend from minor nail dystrophy to severe life-threatening blistering, making early molecular diagnosis and prognostication of utmost importance for the affected families. DEB is caused by mutations in the COL7A1 gene encoding collagen VII in the skin. Molecular diagnostics and genotype-phenotype correlations in DEB remain complex owing to the gene structure, large variety of mutations, high rate of novel mutations, complex protein structure and assembly, and the heterogeneity of phenotypes. Here, we report an efficient strategy for COL7A1 mutation detection using direct automated DNA sequencing and implementation of software tools. With this approach, COL7A1 mutations of 41 DEB families were disclosed. Twenty-four mutations were novel and two recurrent. Elucidation of biological consequences of the mutations helped define disease mechanisms, but also revealed several unusual genotypic and/or phenotypic constellations, which impeded the diagnostics and prognostication. In addition, the studies disclosed a de novo mutation in recessive DEB and two new polymorphisms in the COL7A1 gene.

Collagen Type VII↗

PubMed2000

A de novo glycine substitution mutation in the collagenous domain of COL7A1 in dominant dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa (DEB) is a hereditary mechanobullous disorder characterized by fragility of the skin and mucous membrane due to abnormalities of anchoring fibrils. Both dominant and recessive DEB have been shown to be caused by mutations in COL7A1, the gene encoding type VII collagen which is the major component of anchoring fibrils. De novo mutation in dominant DEB is rare. In this study, we report a novel de novo glycine substitution mutation in COL7A1 in a Chinese female patient presenting with mild DEB. In search of the mutation, we scanned the entire COL7A1 using polymerase chain reaction (PCR) amplification of all exons of COL7A1, followed by heteroduplex analysis and direct sequencing of the PCR products that exhibited heteroduplex pattern. A G-to-A transition at nucleotide position 6082 within exon 73 of COL7Al was detected. The mutation converted a glycine to an arginine (G2028R) within the triple-helical domain of type VII collagen. It was confirmed that the mutation was present only in the proband. Haplotype analyses suggested that the case arose as a de novo occurrence of autosomal dominant DEB.

Alleles↗

PubMed2004

A novel missense mutation in the COL7A1 gene underlies epidermolysis bullosa pruriginosa.

Epidermolysis bullosa (EB) pruriginosa is a subtype of dominant dystrophic EB (DDEB), characterized by severe pruritus and blistering localized to the extensor surface of the extremities. EB pruriginosa exhibits extensive clinical heterogeneity with variable expression and delayed age of onset. Mutations in the COL7A1 gene, especially in glycine residues within Gly-X-Y repeats, have been shown to cause this form of DDEB. Here, we report a novel COL7A1 mutation in a Taiwanese pedigree with EB pruriginosa. Using PCR and direct sequence analysis we have identified a G-->T transversion at nucleotide 7097 in exon 92 of COL7A1, converting a glycine residue to valine (G2366V). The mutation resides within a consecutive, uninterrupted stretch of 17 Gly-X-Y residues in the triple-helical domain of type VII collagen. Interestingly, an affected member of this family also displayed elevated IgE levels, previously reported in some patients with this disorder. Our finding further implicates COL7A1 mutation in the pathogenesis of EB pruriginosa and underscores the heterogeneous clinical symptoms of glycine mutations in DDEB.

Base Sequence↗

PubMed1997

Development of an ELISA for rapid detection of anti-type VII collagen autoantibodies in epidermolysis bullosa acquisita.

Epidermolysis bullosa acquisita (EBA) is an acquired blistering skin disease characterized by the presence of IgG autoantibodies to type VII collagen. EBA autoantibodies recognize four major immunodominant epitopes localized within the amino-terminal, noncollagenous (NC1) domain. In this study, we developed a rapid, quantitative enzyme-linked immunosorbent assay (ELISA) to detect autoantibody activity against the complete NC1 domain of type VII collagen with the use of an eukaryotic-expressed, recombinant human NC1 antigen. With the ELISA, we tested serum from patients with EBA (n = 24), bullous systemic lupus erythematosus (BSLE) (n = 3), bullous pemphigoid (n = 16), pemphigus (n = 11), and normal controls (n = 12). All EBA and BSLE serum, including four sera that were negative by indirect immunofluorescence, demonstrated reactivity with immobilized NC1 in the ELISA. In contrast, none of the sera from healthy control subjects or patients with unrelated blistering skin diseases reacted with NC1. The EBA sera also reacted with recombinant NC1 by immunoblot analysis but with less sensitivity. Thus, the newly developed ELISA using recombinant NC1 is a sensitive, specific assay and a useful tool for rapidly screening EBA and BSLE serum.

Autoantibodies↗

PubMed1994

Immunohistochemical detection of keratin with the monoclonal antibody MNF116 is useful in the diagnosis of epidermolysis bullosa simplex.

Epidermolysis bullosa simplex (EBS) is an uncommon genetic skin disease characterized by fragility of the basal keratinocytes and propensity to develop blisters. While a panel of antibodies against type IV collagen, laminin, and bullous pemphigoid antigen has been used to identify cases of EBS in frozen sections, we have found that a monoclonal antibody detecting cytokeratin in basal keratinocytes is useful in paraffin sections. Formalin-fixed, paraffin-embedded tissues from 12 patients with EBS were studied with the following monoclonal antibodies: MNF116 (DAKO, Carpinteria, CA), CAM 5.2 (Becton Dickinson, San Jose, CA), and AE1-AE3 mixture (Boehringer Mannheim Corp, Indianapolis, IN). Histologically, all the cases had focal vacuolization of the basal cell layer, with areas of dermal-epidermal separation. MNF116 was strongly positive in the basal keratinocytes, including the vacuolated ones, and demonstrated the presence of fragments of keratinocytes attached to the floor of the blister. CAM 5.2 stained sweat ducts only. AE1-AE3 was weakly positive in the basal cells, and almost completely negative on the fragmented basal cell keratinocytes. We consider that the immunostain with MNF116 in tissues fixed routinely in formalin and embedded in paraffin is helpful for the direct demonstration of the level of splitting in EBS.

Antibodies, Monoclonal↗

PubMed2002

Genotype-phenotype correlation in italian patients with dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa (DEB) is a rare skin disorder that is clinically heterogeneous and is transmitted either in dominant (DDEB) or recessive (RDEB) mode. Nevertheless, all variants of DEB are caused by mutations in type VII collagen gene (COL7A1). We report an analysis of COL7A1 mutations in 51 Italian DEB patients, 27 affected with Hallopeau-Siemens RDEB, 19 with non Hallopeau-Siemens RDEB, two with DDEB, two with pretibial RDEB, and one with inversa RDEB. Forty-one mutations were identified, 18 of which are novel. Mutation consequences were analyzed at the mRNA and protein level and genotype-phenotype correlation was determined. Recessive inheritance of a new case of pretibial RDEB was also established. In RDEB patients, six recurrent mutations were identified: 7344G-->A, 425A-->G, 8441-14del21, 4783-1G-->A, 497insA, and G1664A, the last three being found only in Italian patients. Indeed, haplotype analysis supported propagation of ancestral mutated alleles within the Italian population for these particular mutations. Altogether recurrent mutations account for approximately 43% of RDEB alleles in Italian patients and therefore new DEB patients should first be screened for the presence of these mutations.

Collagen Type VII↗

PubMed2005

Evidence that anti-type VII collagen antibodies are pathogenic and responsible for the clinical, histological, and immunological features of epidermolysis bullosa acquisita.

Epidermolysis bullosa acquisita (EBA) is an autoimmune blistering disease characterized by autoantibodies to type VII (anchoring fibril) collagen. Therefore, it is a prototypic autoimmune disease defined by a well-known autoantigen and autoantibody. In this study, we injected hairless immune competent mice with purified immunoglobulin G (IgG) fraction of serum from rabbits immunized with the non-collagenous amino-terminal domain (NC1) of human type VII collagen, the domain known to contain immunodominant epitopes. As a control, identical mice were injected with the IgG fraction of serum from non-immunized rabbits. Mice injected with immune IgG developed subepidermal skin blisters and erosions, IgG deposits at the epidermal-dermal junction of their skin, and circulating anti-NC1 antibodies in their serum-all features reminiscent of patients with EBA. Similar concentrations of control IgG purified from normal rabbits did not induce disease in the mice. These findings strongly suggest that autoantibodies that recognize human type VII collagen in EBA are pathogenic. This murine model, with features similar to the clinical, histological, and immunological features of EBA, will be useful for the fine dissection of immunopathogenic mechanisms in EBA and for the development of new therapeutic interventions.

Animals↗

PubMed1998

A recurrent glycine substitution mutation, G2043R, in the type VII collagen gene (COL7A1) in dominant dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa (DEB) is caused by mutations in the type VII collagen gene (COL7A1). Nearly all cases of dominant DEB are caused by glycine substitution mutations occurring within the triple helical region of type VII collagen, and most of the mutations are unique to individual families. In this study, we identified a patient of Hispanic-Mexican origin with a mild form of DEB, which resulted from a de novo dominant glycine substitution, G2043R, in exon 73 of COL7A1. We also investigated a Scottish family with a three-generation pedigree of dominant DEB, in whom the same glycine to arginine substitution mutation was demonstrated. This particular mutation has also been detected previously in three other families with dominant DEB: one Italian, one Hungarian and one Norwegian. Given the widespread geographical distribution of this mutation and the demonstration of its occurrence as a de novo event, G2043R therefore represents the first example of a mutational hotspot in dominant DEB. Interestingly, although both the Mexican and Scottish families we studied had some clinical features in keeping with the Pasini form of the disorder, there was considerable interfamilial variability as well as intrafamilial diversity in the affected individuals.

Adult↗