Epidermolysis bullosa hereditaria with Junctional Blistering in an Adult

Hashimoto, Isao; Schnyder, U. W.; Anton‐Lamprecht, I.

doi:10.1159/000251166

Cited by 89 publications

(45 citation statements)

References 6 publications

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“…First, generalized atrophic benign EB (GABEB) is characterized by life-long blistering of the skin associated with hair and tooth abnormalities. Traditionally, this subtype has been classified as a nonlethal variant of junctional EB (6,7). It is now known that the majority of patients with GABEB harbor mutations in the type XVII collagen/180-kD bullous pemphigoid antigen gene (COL17A1/BPAG2) (5).…”

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confidence: 99%

Epidermolysis Bullosa with Congenital Pyloric Atresia: Novel Mutations in the β4 Integrin Gene (ITGB4) and Genotype/Phenotype Correlations

et al. 2001

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Epidermolysis bullosa with pyloric atresia (EB-PA: OMIM 226730), also known as Carmi syndrome, is a rare autosomal recessive genodermatosis that manifests with neonatal mucocutaneous fragility associated with congenital pyloric atresia. The disease is frequently lethal within the first year, but nonlethal cases have been reported. Mutations in the genes encoding subunit polypeptides of the ␣6␤4 integrin (ITGA6 and ITGB4) have been demonstrated in EB-PA patients. To extend the repertoire of mutations and to identify genotype-phenotype correlations, we examined seven new EB-PA families, four with lethal and three with nonlethal disease variants. DNA from patients was screened for mutations using heteroduplex analysis followed by nucleotide sequencing of PCR products spanning all ␤4 integrincoding sequences. Mutation analysis disclosed 12 distinct mutations, 11 of them novel. Four mutations predicted a premature termination codon as a result of nonsense mutations or small out-of-frame insertions or deletions, whereas seven were missense mutations. This brings the total number of distinct ITGB4 mutations to 33. The mutation database indicates that premature termination codons are associated predominantly with the lethal EB-PA variants, whereas missense mutations are more prevalent in nonlethal forms. However, the consequences of the missense mutations are position dependent, and substitutions of highly conserved amino acids may have lethal consequences. In general, indirect immunofluorescence studies of affected skin revealed negative staining for ␤4 integrin in lethal cases and positive, but attenuated, staining in nonlethal cases and correlated with clinical phenotype. The data on specific mutations in EB-PA patients allows prenatal testing and preimplantation genetic diagnosis in families at risk. Abbreviations EB-PA, epidermolysis bullosa with pyloric atresia BMZ, basement membrane zone CSGE, conformation-sensitive gel electrophoresis PTC, premature termination codon TEM, transmission electron microscopy ITGB4, ␤4 integrin gene Epidermolysis bullosa (EB) is a group of genodermatoses manifesting with blistering and erosions of the skin and mucous membranes as a result of mechanical trauma (1, 2). The clinical severity of EB is highly variable. In the mildest cases, blistering occurs primarily on the hands and feet with relatively little morbidity, whereas, in the most severe cases, the disease can be lethal perinatally or during the early postnatal period. Traditionally, EB has been divided into three broad categories based on clinical findings and ultrastructural demonstrations of

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confidence: 99%

Epidermolysis Bullosa with Congenital Pyloric Atresia: Novel Mutations in the β4 Integrin Gene (ITGB4) and Genotype/Phenotype Correlations

et al. 2001

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“…Blistering was generalized and blisters often occurred in groups and most frequently on the limbs (but not particularly over bends). The lesions healed without scarring or milia but with atrophic skin to variable degrees, and some pigmented maculae closely resembling those in the phenotype known as GABEB (Hashimoto et al, 1976;Hintner and Wolff, 1982).…”

Section: Patientmentioning

confidence: 83%

“…In only one (Schumann et al, 1997) of the patients could type XVII collagen be immunologically detected in skin or cultured keratinocytes. The phenotype of JEB-nH caused by type XVII collagen deficiency may vary from generalized blistering with alopecia, also known as generalized atrophic benign epidermolysis bullosa (GABEB) (Hashimoto et al, 1976;Hintner and Wolff, 1982;Jonkman et al, 1996), to mild localized blistering without loss of hair (Floeth et al, 1998;Mazzanti et al, 1998;Schumann et al, 1997).In this study, we report for the first time homozygosity for a donor splice-site mutation in COL17A1 leading to multiple aberrant mRNA in a patient with generalized JEB-nH. The most abundant mRNA has an internal deletion of 390 bp, which leads to the expression of a shortened nonfunctional type XVII collagen polypeptide with a 130 amino acid deletion in the carboxy terminal half.…”

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confidence: 99%

Truncated Type XVII Collagen Expression in a Patient with Non-Herlitz Junctional Epidermolysis Bullosa Caused by a Homozygous Splice-Site Mutation

Leusden

Pas

Gedde‐Dahl

et al. 2001

Laboratory Investigation

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SUMMARY:Type XVII collagen (180-kDa bullous pemphigoid antigen) is a structural component of hemidesmosomes.Mutations in the type XVII collagen gene (COL17A1) have been established to be the molecular basis of non-Herlitz junctional epidermolysis bullosa (JEB-nH), an inherited skin blistering disorder. Here we report for the first time truncated type XVII collagen expression, caused by homozygosity for a COL17A1 donor splice-site mutation (4261ϩ1 g 3 c), which was identified by PCR amplification on genomic DNA. By RT-PCR and sequencing of cDNA derived from mRNA from the patient's cultured keratinocytes, we provide evidence of cryptic splicing and exon skipping, most abundantly of exon 52. JEB-nH patients with COL17A1 splice-site mutations resulting in an exon skip often have no immunologically detectable type XVII collagen. However, in our patient with the generalized atrophic benign epidermolysis bullosa subtype, a small amount of type XVII collagen was detectable in the skin, and immunoblotting of cultured keratinocytes revealed that the 180-kDa protein was 10 kDa shorter. We hypothesize that the function of this truncated type XVII collagen polypeptide, which is expressed at low levels, is impaired, explaining the JEB-nH phenotype. (Lab Invest 2001, 81:887-894).T ype XVII collagen (180-kDa bullous pemphigoid antigen; BP180, BPAG2), encoded by the COL17A1 gene, plays a critical role in adhesion of basal keratinocytes to the epidermal basement membrane zone (EBMZ). Its expression is restricted to hemidesmosomes, morphological structures that mediate the adhesion of basal keratinocytes to the underlying EBMZ in stratified and pseudostratified epithelia. Type XVII collagen interacts with other hemidesmosomal components (eg, the ␣6␤4 integrin and 230-kDa bullous pemphigoid antigen [BP230]), and thereby plays a role in the assembly and stabilization of hemidesmosomes (Hopkinson and Jones, 2000;Schaapveld et al, 1998). The molecule is a type II transmembrane protein whose carboxy terminal end is located outside the cell. This extracellular part contains 15 collagenous domains (COL1-15), interspaced by noncollagenous domains (NC1-16) (Giudice et al, 1992), which gives the molecule a certain flexibility. By electron microscopy, type XVII collagen is seen as a rigid central rod (COL15) followed by a movable tail (Hirako et al, 1996). Like other collagens, the molecule is able to trimerize by self assembly in such a way that the extracellular fragment forms a triple helix, ␣1[XVII] 3 (Balding et al, 1997;Hirako et al, 1996;Pas et al, 1999). The length of the rod domain is sufficient to traverse the lamina lucida, and the flexible carboxyl terminus has been seen within the lamina densa (Shimizu, 1998). Its as yet unidentified ligand(s) may reside within the lamina densa or lamina lucida. A candidate ligand is laminin 5, which is mainly localized in the upper lamina densa (Shimizu, 1998). An interaction between the extracellular domain of type XVII collagen and laminin 5 has been reported (Reddy et al, 1998). The globular...

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“…GABEB was initially described as a nonlethal variant of junctional EB (96,97). Clinically, the affected individuals demonstrate protracted, life-long generalized blistering which results in cutaneous atrophy, associated with diffuse scarring alopecia, characteristic pigmentary changes, as well as tooth and nail abnormalities.…”

Section: Clinical Features and Molecular Basis Of General-ized Atrophmentioning

confidence: 99%

Hemidesmosomal variants of epidermolysis bullosa

Pulkkinen

Uitto

1998

Experimental Dermatology

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Mutations in the a 6 b 4 integrin and the 180-kD bullous pemphigoid antigen/type XVII collagen genes Pulkkinen L, Uitto J. Hemidesmosomal variants of epidermolysis bullosa. L. Pulkkinen and J. UittoMutations in the a 6 b 4 integrin and the 180-kD bullous pemphigoid anti- matoses, is characterized by fragility and blistering of the skin, associated with characteristic extracutaneous manifestations. Based on clinical severity, constellation of the phenotypic manifestations, and the level of tissue separation within the cutaneous basement membrane zone, EB has been divided into distinct subcategories. Traditionally, these include the simplex, junctional and dystrophic variants of EB. Recent attention has been drawn to variants of EB demonstrating tissue separation at the level of hemidesmosomes, ultrastructurally recognizable adhesion complexes within the cutaneous basement membrane zone. Clinically, these hemidesmosomal variants manifest either as generalized atrophic benign epidermolysis bullosa (GABEB), EB with pyloric atresia, or EB with late-onset muscular dystrophy. Elucidation of basement membrane zone components by molecular cloning and development of mutation detection strat-

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Epidermolysis bullosa hereditaria with Junctional Blistering in an Adult

Cited by 89 publications

References 6 publications

Epidermolysis Bullosa with Congenital Pyloric Atresia: Novel Mutations in the β4 Integrin Gene (ITGB4) and Genotype/Phenotype Correlations

Epidermolysis Bullosa with Congenital Pyloric Atresia: Novel Mutations in the β4 Integrin Gene (ITGB4) and Genotype/Phenotype Correlations

Truncated Type XVII Collagen Expression in a Patient with Non-Herlitz Junctional Epidermolysis Bullosa Caused by a Homozygous Splice-Site Mutation

Hemidesmosomal variants of epidermolysis bullosa

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