Amino acid substitution in the C-terminal domain of collagen XVII reduces laminin-332 interaction causing mild skin fragility with atrophic scarring

Kroeger, Jasmin K.; Hoppe, Esther; Galiger, Célimène; Has, Cristina; Franzke, Claus‐Werner

doi:10.1016/j.matbio.2018.10.003

Cited by 14 publications

(19 citation statements)

References 39 publications

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“…It also translates into a PTC, p.R1226 * . This recurrent mutation has also been previously reported in Dutch population (24) and leads to nonsense mediated mRNA decay, demonstrated by absence of full length collagen XVII (12, 25). Next, we found c.2062C > T, p.R688 * , c.2861delG, p.G954Afs * 112 and 418_419delAG, p.S140 * to represent 4.41% of the mutant alleles in 4.31% of our patients.…”

Section: Resultssupporting

confidence: 74%

“…All these null-mutations lead to absence of type XVII collagen and generalized intermediate JEB (previously known as generalized atrophic benign epidermolysis bullosa (GABEB) and later as non-Herlitz JEB). This most severe COL17A1 -associated phenotype was the first to be recognized (12, 17, 22). The main clinical manifestation is represented by mechanically induced skin blistering that starts at birth, is generalized and persists lifelong, without spontaneous improvement.…”

Section: Resultsmentioning

confidence: 97%

“…This mutation also appears to hamper the physiological C-terminal cleavage of type XVII collagen. Consequently, non-cleaved type XVII collagen ectodomain remnants induce the aberrant deposition of laminin-332 in the extracellular matrix (12, 22). Clinically, p.R1303Q is associated with a mild, Kindler-syndrome-like phenotype, manifesting with late onset skin blistering, progressive skin atrophy and sclerosis, loss of dermatoglyphics, scarring, and nail anomalies.…”

Section: Resultsmentioning

confidence: 99%

“…After informed consent genomic DNA was extracted from EDTA-blood using the Qiagen blood minikit (Qiagen, Hilden Germany). In most cases, mutation analysis was performed by bidirectional Sanger sequencing as reported before (12). Targeted next generation sequencing (NGS) of EB genes was performed since 2016 as described (13).…”

Section: Methodsmentioning

confidence: 99%

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Junctional Epidermolysis Bullosa: Allelic Heterogeneity and Mutation Stratification for Precision Medicine

Condrat

Cosgarea

et al. 2019

Front. Med.

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Junctional epidermolysis bullosa (JEB) is a hereditary blistering disease caused by reduced dermal-epidermal adhesion due to deficiencies of one of the proteins, laminin-332, type XVII collagen, integrin α6β4 or integrin α3. Significant progress has been achieved in the development of therapies for EB, such as bone-marrow transplantation, local or systemic injections with fibroblasts or mesenchymal stromal cells, readthrough of premature termination codons, or exon skipping. These were tailored in particular for dystrophic EB, which is caused by type VII collagen deficiency and have not yet reached broad clinical practice. Recently, pioneering combined gene and stem cell therapy was successful in treating one boy with junctional EB. Beside these exclusive approaches, no specific therapy to amend the major clinical features, skin and mucosal blistering and non-healing wounds is available to date. Here we extend the mutational spectrum of junctional EB, provide a stratification of COL17A1 mutations and discuss potential molecular therapeutic approaches.

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Section: Resultssupporting

confidence: 74%

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Junctional Epidermolysis Bullosa: Allelic Heterogeneity and Mutation Stratification for Precision Medicine

Condrat

Cosgarea

et al. 2019

Front. Med.

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“…They almost certainly prevent formation of functional laminin-332 or may foster formation of granulation tissue and impaired wound healing. 31,32 In mice 33 and potentially in humans, 34 some allelic variants of the collagen XVII ectodomain represent major genetic modifiers of JEB caused by abnormal laminin-332, as they may reduce the strength of dermal-epidermal adhesion in the context of a mutation in laminin-332 genes. Such phenotypic modification was excluded in our patients.…”

Section: Discussionmentioning

confidence: 99%

Aberrant splicing as potential modifier of the phenotype of junctional epidermolysis bullosa

Mittwollen

Wohlfart

Park

et al. 2020

Acad Dermatol Venereol

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Background A lack or dysfunction of the anchoring protein laminin‐332 in the basement membrane leads to the skin blistering disorder junctional epidermolysis bullosa (JEB). The mutation c.628G>A in the gene LAMB3 encoding the laminin β3‐chain is associated with generalized intermediate JEB; it may introduce an amino acid substitution (p.Glu210Lys) or disrupt splicing. Objective This retrospective study aimed at determining the effects of aberrant splicing on the JEB phenotype. Methods LAMB3 transcription was analysed in two siblings compound heterozygous for the LAMB3 mutations p.Glu210Lys and p.Arg635* with a diverging JEB phenotype from late childhood on. Laminin‐332 levels in skin sections and in cultured keratinocytes were investigated by immunofluorescence staining. Real‐time PCR was used to quantify LAMB3 expression in keratinocytes. RNA splice variants were identified by subcloning of a LAMB3 cDNA fraction and subsequent DNA sequencing. Structural models of laminin‐332 helped to assess the impact of certain mutations on laminin‐332 folding. Results Both siblings showed diminished LAMB3 expression. Laminin‐332 was equally reduced in skin sections obtained during infancy but differed in keratinocytes isolated during adolescence. Although aberrant LAMB3 splicing with 26 variants was detected in both patients, splicing differed significantly: the full‐length LAMB3 transcript harbouring the p.Glu210Lys mutation was found more often in the patient affected less severely (14/108 vs. 5/106 clones; P = 0.03). Structural modelling predicted that several deletions in LAMB3, but not the point mutation p.Glu210Lys, have an effect on laminin‐332 folding and secretion. Conclusions Differential LAMB3 mRNA splicing in the patients may explain the disparate JEB phenotype. By elucidating the regulation of laminin‐332 gene expression, these findings may contribute to the development of therapeutic strategies for JEB and might help to understand phenotype modification by splice‐site mutations in other hereditary diseases.

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Modulation of Macrophages by In Situ Ligand Bridging

Kim

Thangam

Kang

et al. 2023

Adv Funct Materials

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Extracellular matrix (ECM) proteins containing cell-attachableArg-Gly-Asp (RGD) sequences exhibit variable bridging and non-bridging in fibronectincollagen and laminin-collagen complexes that can regulate inflammation, tissue repair, and wound healing. In this study, linking molecule-mediated conjugation of 1D magnetic nanocylinders (MNCs) to material surfaces pre-decorated with gold nanospheres (GNSs) is performed, thereby yielding RGD-coated MNCs (RGD-MNCs) over RGD-coated GNSs (RGD-GNSs) in a non-bridging state. The RGD-MNCs are drawn closer to the RGD-GNSs via magnetic field-mediated compression of the linking molecules to establish the bridging between them. Relative proportion of the RGD-MNCs to the RGD-GNSs is optimized to yield effective remote stimulation of integrin binding to variably bridged RGDs similar to that of invariably bridged RGDs used as a control group. Remote manipulation of the RGD bridging facilitates the attachment structure assembly of macrophages that leads to pro-healing/ anti-inflammatory phenotype acquisition. In contrast, the non-bridged RGDs inhibited macrophage attachment that acquired pro-inflammatory phenotypes. The use of various nanomaterials in constructing heterogeneous RGDcoated materials can further offer various modes in remote switching of RGD bridging and non-bridging to understand dynamic integrin-mediated modulation of macrophages that regulate immunomodulatory responses, such as foreign body responses, tissue repair, and wound healing.

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Amino acid substitution in the C-terminal domain of collagen XVII reduces laminin-332 interaction causing mild skin fragility with atrophic scarring

Cited by 14 publications

References 39 publications

Junctional Epidermolysis Bullosa: Allelic Heterogeneity and Mutation Stratification for Precision Medicine

Junctional Epidermolysis Bullosa: Allelic Heterogeneity and Mutation Stratification for Precision Medicine

Aberrant splicing as potential modifier of the phenotype of junctional epidermolysis bullosa

Modulation of Macrophages by In Situ Ligand Bridging

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