Expression of Integrin α6β4 in Junctional Epidermolysis Bullosa

Jonkman, Marcel F.; Jong, M. C. J. M. de; Heeres, K; Sonnenberg, Arnoud

doi:10.1111/1523-1747.ep12616168

Cited by 60 publications

(39 citation statements)

References 41 publications

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“…The category generalized JEB mitis has not yet been split into subtypes and is also referred to as generalized atrophic benign epidermolysis bullosa (GABEB) (15) (27).…”

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confidence: 99%

“…The a6 integrin subunit was stained with our moabs GoH3 (23) Immunofluorescence procedures. 4-,um cryostat sections of skin specimens were processed for immunofluorescence as previously described (27). Fluorescence overlay antigen mapping was performed as recently described (27,28).…”

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confidence: 99%

“…4-,um cryostat sections of skin specimens were processed for immunofluorescence as previously described (27). Fluorescence overlay antigen mapping was performed as recently described (27,28). Digital video microscopic images of tissue sections were obtained with a newly developed imaging system with long exposure times designed for the detection of very low levels of fluorescence (29).…”

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confidence: 99%

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180-kD bullous pemphigoid antigen (BP180) is deficient in generalized atrophic benign epidermolysis bullosa.

Jonkman¹,

Jong²,

Heeres³

et al. 1995

J. Clin. Invest.

163

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IntroductionGeneralized atrophic benign epidermolysis bullosa (GA-BEB) is a form of nonlethal junctional epidermolysis bullosa characterized by universal alopecia and atrophy of the skin. We report a deficiency of the 180-kD bullous pemphigoid antigen in three patients with GABEB from unrelated families. We screened specimens of clinically normal skin from nine junctional epidermolysis bullosa patients (3 GABEB, 4 lethal, 1 cicatricial, 1 pretibial) by immunofluorescence using monoclonal antibodies to the 180-kD and 230-kD bullous pemphigoid antigens (BP180 and BP230). In the skin of the three GABEB patients there was no reactivity with antibodies to BP180, whereas staining for BP230 was normal. In the skin of the other six, non-GABEB patients, included in this study the expression of BP180 and BP230 was normal. Immunoblot analysis of cultured keratinocytes from one of the GABEB patients also failed to detect BP180 antigen, whereas BP230 was present in normal amounts. In previous studies on the expression of the bullous pemphigoid antigen in JEB, sera from bullous pemphigoid (BP) patients were used, the specificity of which had not been analyzed by immunoblotting (6-9). The expression was found to be normal or variable. Later it became apparent that BP-serum is a mixture of polyclonal antibodies, which are very difficult to characterize, even after affinity-purification (10). Fortunately, reliable monospecific antibodies for each of the two major bullous pemphigoid antigens have now become available (1 1, 12).In this study we used monoclonal antibodies specific for BPI 80 and BP230 (11,12). In addition we studied the expression of the newly described 500-kD hemidesmosomal plaque protein HD1 (13)

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“…The category generalized JEB mitis has not yet been split into subtypes and is also referred to as generalized atrophic benign epidermolysis bullosa (GABEB) (15) (27).…”

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confidence: 99%

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confidence: 99%

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confidence: 99%

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180-kD bullous pemphigoid antigen (BP180) is deficient in generalized atrophic benign epidermolysis bullosa.

Jonkman¹,

Jong²,

Heeres³

et al. 1995

J. Clin. Invest.

163

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“…We harvested and processed skin specimens for immunofluorescence antigen mapping (IF) and transmission electron microscopy (TEM) of the JEB index patients as described before. 6,7 IF and TEM were not performed in carriers, as no biopsies were available. Genomic DNA was isolated from peripheral blood from the index patients and parents, and sequenced using Sanger's sequencing by a candidate gene approach.…”

Section: Methodsmentioning

confidence: 99%

Carriers with functional null mutations in LAMA3 have localized enamel abnormalities due to haploinsufficiency

Gostyńska¹,

Yuen²,

Pasmooij³

et al. 2016

Eur J Hum Genet

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The hereditary blistering disease junctional epidermolysis bullosa (JEB) is always accompanied by structural enamel abnormalities of primary and secondary dentition, characterized as amelogenesis imperfecta. Autosomal recessive mutations in LAMA3, LAMB3 and LAMC2 encoding the heterotrimer laminin 332 (LM-332) are among the genes causing JEB. While examining pedigrees of JEB patients with LAMA3 mutations, we observed that heterozygous carriers of functional null mutations displayed subtle enamel pitting in the absence of skin fragility or other JEB symptoms. Here, we report two new LAMA3 functional null mutations: nonsense c.2377C4T p.(Arg793Ter) and splice-site c.4684+1G4A mutation in heterozygous carriers exhibiting enamel pitting. Both parents had offspring affected with JEB and displayed subtle enamel pitting of secondary dentition without any sign of skin blistering. The reported enamel abnormality in LAMA3 mutation carriers could be attributed to a half dose effect of the laminin α3 chain (haploinsufficiency).

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“…Cryostat sections (4 m) of skin specimens were processed for immunofluorescence as described previously (Jonkman et al, 1992). In combination with the primary mouse monoclonal antibodies, biotinylated goat antimouse IgG1, in a dilution 1:100 (SBA, Birmingham, Alabama), and DTAF (dichlorotriazinylamino-fluorescein)-conjugated streptavidin, in a dilution 1:200 (Jackson Immuno Research, West Grove, Pennsylvania), were used in secondary and tertiary steps.…”

Section: Immunofluorescence Studiesmentioning

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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Expression of Integrin α6β4 in Junctional Epidermolysis Bullosa

Cited by 60 publications

References 41 publications

180-kD bullous pemphigoid antigen (BP180) is deficient in generalized atrophic benign epidermolysis bullosa.

180-kD bullous pemphigoid antigen (BP180) is deficient in generalized atrophic benign epidermolysis bullosa.

Carriers with functional null mutations in LAMA3 have localized enamel abnormalities due to haploinsufficiency

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

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