scholarly journals Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility

2020 ◽  
Vol 183 (4) ◽  
pp. 614-627 ◽  
Author(s):  
C. Has ◽  
J.W. Bauer ◽  
C. Bodemer ◽  
M.C. Bolling ◽  
L. Bruckner‐Tuderman ◽  
...  
Keyword(s):  
Epidermolysis Bullosa ◽  
Inherited Epidermolysis Bullosa ◽  
Skin Fragility

scholarly journals Advances in understanding the molecular basis of skin fragility

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 279 ◽  
Author(s):  
Cristina Has
Keyword(s):  
Epidermolysis Bullosa ◽  
Molecular Basis ◽  
Molecular Mechanisms ◽  
Genetic Disorders ◽  
Scientific Progress ◽  
Mechanical Trauma ◽  
Therapeutic Approaches ◽  
New Genes ◽  
Inherited Epidermolysis Bullosa ◽  
Skin Fragility

Skin fragility refers to a large group of conditions in which the ability of the skin to provide protection against trivial mechanical trauma is diminished, resulting in the formation of blisters, erosions, wounds, or scars. Acquired and physiological skin fragility is common; genetic disorders are rare but give insight into the molecular mechanisms ensuring skin stability. The paradigm is represented by inherited epidermolysis bullosa. This review is focused on recent advances in understanding the molecular basis of genetic skin fragility, including emerging concepts, controversies, unanswered questions, and opinions of the author. In spite of the advanced knowledge on the genetic causes of skin fragility, the molecular pathology is still expanding. Open questions in understanding the molecular basis of genetic skin fragility are the following: what are the causes of phenotypes which remain genetically unsolved, and what are the molecular modifiers which might explain phenotypic differences among individuals with similar mutations?  New mutational mechanisms and new genes have recently been discovered and are briefly described here. Comprehensive next-generation sequencing-based genetic testing improved mutation detection and facilitated the identification of the genetic basis of unclear and new phenotypes. Characterization of the biochemical and cell biological consequences of the genetic variants is challenging and laborious but may represent the basis for personalized therapeutic approaches. Molecular modifiers of skin fragility have been uncovered in particular animal and genetic models but not in larger cohorts of patients. This scientific progress is the basis for revisions of the epidermolysis bullosa classification and for innovative therapeutic approaches designed for this intractable condition.

scholarly journals A Novel Phenotype of Junctional Epidermolysis Bullosa with Transient Skin Fragility and Predominant Ocular Involvement Responsive to Human Amniotic Membrane Eyedrops

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 716
Author(s):  
Daniele Castiglia ◽  
Paola Fortugno ◽  
Angelo Giuseppe Condorelli ◽  
Sabina Barresi ◽  
Naomi De Luca ◽  
...  
Keyword(s):  
Amniotic Membrane ◽  
Epidermolysis Bullosa ◽  
Ocular Involvement ◽  
Human Amniotic Membrane ◽  
Vitro Assay ◽  
Junctional Epidermolysis Bullosa ◽  
Mucosal Involvement ◽  
Skin Fragility ◽  
Laminin 332

Junctional epidermolysis bullosa (JEB) is a clinically and genetically heterogeneous skin fragility disorder frequently caused by mutations in genes encoding the epithelial laminin isoform, laminin-332. JEB patients also present mucosal involvement, including painful corneal lesions. Recurrent corneal abrasions may lead to corneal opacities and visual impairment. Current treatments are merely supportive. We report a novel JEB phenotype distinguished by the complete resolution of skin fragility in infancy and persistent ocular involvement with unremitting and painful corneal abrasions. Biallelic LAMB3 mutations c.3052-5C>G and c.3492_3493delCG were identified as the molecular basis for this phenotype, with one mutation being a hypomorphic splice variant that allows residual wild-type laminin-332 production. The reduced laminin-332 level was associated with impaired keratinocyte adhesion. Then, we also investigated the therapeutic power of a human amniotic membrane (AM) eyedrop preparation for corneal lesions. AM were isolated from placenta donors, according to a procedure preserving the AM biological characteristics as a tissue, and confirmed to contain laminin-332. We found that AM eyedrop preparation could restore keratinocyte adhesion in an in vitro assay. Of note, AM eyedrop administration to the patient resulted in long-lasting remission of her ocular manifestations. Our findings suggest that AM eyedrops could represent an effective, non-invasive, simple-to-handle treatment for corneal lesions in patients with JEB and possibly other EB forms.

scholarly journals Mouse models for dominant dystrophic epidermolysis bullosa (DDEB) carrying common human point mutations recapitulate the human disease

2021 ◽  
Author(s):  
B. R. C. Smith ◽  
A. Nystrom ◽  
C. J. Nowell ◽  
I. Hausser ◽  
C. Gretzmeier ◽  
...  
Keyword(s):  
Mouse Models ◽  
Epidermolysis Bullosa ◽  
Severe Disease ◽  
Point Mutations ◽  
Missense Mutations ◽  
Dystrophic Epidermolysis Bullosa ◽  
Mild Phenotype ◽  
Growth And Survival ◽  
Skin Fragility ◽  
Collagen Vii

Heterozygous missense mutations in the human COL7A1 gene – coding for collagen VII – lead to the rare, dominantly inherited skin disorder dominant dystrophic epidermolysis bullosa (DDEB) that is characterized by skin fragility, blistering, scarring and nail dystrophy. To better understand the pathophysiology of DDEB and develop more effective treatments, suitable mouse models for DDEB are required but to date none have existed. We identified the two most common COL7A1 mutations in DDEB patients (p.G2034R and p.G2043R) and used CRISPR to introduce the corresponding mutations into mouse Col7a1 (p.G2028R and p.G2037R). Dominant inheritance of either of these two alleles results in a phenotype that closely resembles that seen in DDEB patients. Specifically, mice carrying these alleles show recurrent blistering that is first observed transiently around the mouth and paws in the early neonatal period and then again around the digits from 5-10 weeks of age. Histologically, the mice show micro-blistering and reduced collagen VII immunostaining. Biochemically, collagen VII from these mice displays reduced thermal stability, which we also observed to be the case for DDEB patients carrying the analogous mutations. Unlike previous rodent models of EB which frequently show early lethality and severe disease, these mouse models which to our knowledge are the first for DDEB show no reduction in growth and survival and – together with a relatively mild phenotype – represent a practically and ethically tractable tool for better understanding and treating EB.

Dystrophic form of inherited epidermolysis bullosa in a dog (Akita Inu)

1995 ◽  
Vol 133 (6) ◽  
pp. 1000-1003 ◽  
Author(s):  
M. NAGATA ◽  
H. SHIMIZU ◽  
T. MASUNAGA ◽  
T. NISHIKAWA ◽  
H. NANKO ◽  
...  
Keyword(s):  
Epidermolysis Bullosa ◽  
Inherited Epidermolysis Bullosa

scholarly journals Impaired lymphoid extracellular matrix impedes antibacterial immunity in epidermolysis bullosa

2018 ◽  
Vol 115 (4) ◽  
pp. E705-E714 ◽  
Author(s):  
Alexander Nyström ◽  
Olivier Bornert ◽  
Tobias Kühl ◽  
Christine Gretzmeier ◽  
Kerstin Thriene ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Epidermolysis Bullosa ◽  
Bacterial Colonization ◽  
Mouse Skin ◽  
Innate Immune ◽  
Macrophage Response ◽  
Skin Fragility ◽  
Human Validation ◽  
Spleen And Lymph Nodes ◽  
Collagen Vii

Genetic loss of collagen VII causes recessive dystrophic epidermolysis bullosa (RDEB), a skin fragility disorder that, unexpectedly, manifests also with elevated colonization of commensal bacteria and frequent wound infections. Here, we describe an unprecedented systemic function of collagen VII as a member of a unique innate immune-supporting multiprotein complex in spleen and lymph nodes. In this complex, collagen VII specifically binds and sequesters the innate immune activator cochlin in the lumen of lymphoid conduits. In genetic mouse models, loss of collagen VII increased bacterial colonization by diminishing levels of circulating cochlin LCCL domain. Intraperitoneal injection of collagen VII, which restored cochlin in the spleen, but not in the skin, reactivated peripheral innate immune cells via cochlin and reduced bacterial skin colonization. Systemic administration of the cochlin LCCL domain was alone sufficient to diminish bacterial supercolonization of RDEB mouse skin. Human validation demonstrated that RDEB patients displayed lower levels of systemic cochlin LCCL domain with subsequently impaired macrophage response in infected wounds. This study identifies an intrinsic innate immune dysfunction in RDEB and uncovers a unique role of the lymphoid extracellular matrix in systemic defense against bacteria.

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