A homozygous insertion–deletion in the type VII collagen gene (COL7A1) in Hallopeau–Siemens dystrophic epidermolysis bullosa

Hilal, Latifa; Rochat, Ariane; Duquesnoy, Philippe; Blanchet-Bardon, C; Wechsler, Janine; Martin, Nancy L.; Christiano, A. M.; Barrandon, Yann; Uitto, Jouni; Goossens, Michel

doi:10.1038/ng1193-287

Cited by 124 publications

(72 citation statements)

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“…Approximately 300 distinct COL7A1 mutations have been identified in patients with DEB around the world, and the clinical features, severity, prognosis, and response to treatment vary depending on the specific mutation. 15,24,[27][28][29][30][31] Our understanding of how specific mutations produce differing clinical presentations and prognoses is limited. We believe that our systems have the advantage of being able to use human genes.…”

Section: Discussionmentioning

confidence: 99%

“…In the literature, genomic PTC mutations in COL7A1 were previously reported to result in nonsense-mediated mRNA decay and absence of COL7 protein synthesis in severe generalized cases of RDEB. 24,25 Whether a genomic PTC mutation leads to nonsense-mediated mRNA decay depends on the mutation site. 26 In contrast, the PTC mutation in cDNA does not lead to mRNA decay and is thought to generate a truncated protein.…”

Section: Discussionmentioning

confidence: 99%

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Keratinocyte-/Fibroblast-Targeted Rescue of Col7a1-Disrupted Mice and Generation of an Exact Dystrophic Epidermolysis Bullosa Model Using a Human COL7A1 Mutation

Ito

Sawamura

Goto

et al. 2009

The American Journal of Pathology

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Recessive dystrophic epidermolysis bullosa (RDEB) is a severe hereditary bullous disease caused by mutations in COL7A1, which encodes type VII collagen (COL7). Col7a1 knockout mice (COL7 m؊/؊ ) exhibit a severe RDEB phenotype and die within a few days after birth. Toward developing novel approaches for treating patients with RDEB, we attempted to rescue COL7 m؊/؊ mice by introducing human COL7A1 cDNA. We first generated transgenic mice that express human COL7A1 cDNA specifically in either epidermal keratinocytes or dermal fibroblasts. We then performed transgenic rescue experiments by crossing these transgenic mice with COL7 m؉/؊ heterozygous mice. Surprisingly, human COL7 expressed by keratinocytes or by fibroblasts was able to rescue all of the abnormal phenotypic manifestations of the COL7 m؊/؊ mice, indicating that fibroblasts as well as keratinocytes are potential targets for RDEB gene therapy. Furthermore, we generated transgenic mice with a premature termination codon expressing truncated COL7 protein and performed the same rescue experiments. Notably, the COL7 m؊/؊ mice rescued with the human COL7A1 allele were able to survive despite demonstrating clinical manifestations very similar to those of human RDEB, indicating that we were able to generate surviving animal models of RDEB with a mutated human COL7A1 gene. This model has great potential for future research into the pathomechanisms of dystrophic epidermolysis bullosa and the development of gene therapies for patients with dystrophic epidermolysis bullosa. Dystrophic epidermolysis bullosa (DEB) is clinically characterized by mucocutaneous blistering in response to minor trauma, followed by scarring and nail dystrophy. The blistering occurs along the epidermal basement membrane zone (BMZ) just beneath the lamina densa at the level of the anchoring fibrils. The inheritance of DEB can be autosomal dominant (DDEB) or autosomal recessive (RDEB), each comprising subtypes of different clinical presentations and severities.1 Both DDEB and RDEB are known to be caused by mutations in the COL7A1 gene encoding type VII collagen (COL7), the major component of anchoring fibrils.2 The most severe RDEB subtype, the Hallopeau-Siemens subtype, shows a complete lack of expression of type VII collagen, whereas a less severe RDEB subtype, the non-Hallopeau-Siemens subtype, shows some collagen expression. The clinical fea-

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Keratinocyte-/Fibroblast-Targeted Rescue of Col7a1-Disrupted Mice and Generation of an Exact Dystrophic Epidermolysis Bullosa Model Using a Human COL7A1 Mutation

Ito

Sawamura

Goto

et al. 2009

The American Journal of Pathology

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“…The pathogenic role of AFs in stabilizing the BMZ has been confirmed by EM observations of them being abnormal, diminished or absent, and by the immunohistochemical finding that type VII collagen is reduced or absent in the group of inherited skin diseases collectively known as dystrophic EB (19)(20)(21)(22). All forms of dystrophic EB were recently found to be directly caused by mutations in the type VII collagen gene (COL7A1) (23)(24)(25)(26). Conversely, acquired production of autoantibodies to AFs directed against the NC-1 domain of type VII collagen, leads to EB acquisita, an autoimmune blistering disease (27).…”

Section: I) Anchoring Fibrils (Afs) Originate and Terminate In The Lamentioning

confidence: 70%

New insights into the immunoultrastructural organization of cutaneous basement membrane zone molecules

Shimizu

1998

Experimental Dermatology

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The epidermal basement membrane zone (BMZ) is composed of various molecules, each of which plays an important role in dermoepidermal adhesion. Genetic abnormality of certain BMZ molecules leads to an inherited group of skin diseases collectively referred to as epidermolysis bullosa, whose hallmark is skin fragility of varying degrees. Furthermore, development of autoantibodies to certain BMZ molecules leads to the onset of a number of acquired autoimmune blistering diseases in which dermo-epidermal separation occurs, including bullous pemphigoid and epidermolysis bullosa acquisita. The ultrastructural location of each BMZ molecule has been studied using a range of immunoelectron microscopy (immuno-EM) techniques. Recent technical advances in imKey words: immunoelectron microscopymuno-EM and in molecular engineering for production of epitope-speci- to these findings, this review focuses on three major BMZ-related mol-

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“…The pathogenesis of RDEB involves mutations of the COL7A1 gene encoding type VII collagen (Col7), which is synthesized by both basal keratinocytes and dermal fibroblasts in human skin 1) 2) . Col7 is the main constituent of anchoring fibrils that anchor the epidermal basement membrane to the papillary dermis 3) . Thus, patients with RDEB experience blistering and repeated wounding of the skin, oral mucosa, and gastrointestinal tract 4) 5) .…”

Section: Recessive Dystrophic Epidermolysis Bullosamentioning

confidence: 99%

Adipose-Derived Stromal/Stem Cells for the Treatment of Skin Diseases

Hasegawa

2017

Juntendo Medical Journal

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Recessive dystrophic epidermolysis bullosa (RDEB) is the most severe form of epidermolysis bullosa, a group of genetic skin fragility disorders. Blisters, skin erosion, and scars form all over the body, including mucous membranes in patients with RDEB. The pathogenesis of RDEB involves mutations of the COL7A1 gene encoding type VII collagen, the main constituent of anchoring fibrils that attach the epidermis to the dermis. Persistent skin erosion frequently results in intractable ulcers. As the ulcers heal, they result in severe scarring. Long-term inflammation of skin ulcers all over the body may cause secondary amyloidosis leading to chronic renal failure. In addition, patients with RDEB are at a high risk of skin cancer. Although there is no curative therapy for patients with RDEB, various kinds of biological dressings, including cultured skin substitutes, have been employed for the treatment of intractable ulcers. Nonetheless, allogeneic cultured skin cannot be permanently adopted. Autologous cultured skin lacks type VII collagen. Adipose-derived stromal/stem cells (ASCs) are easily harvested in large quantities from a minimal donor site, and show less immunogenicity and a powerful immunosuppressive potential.In addition, ASCs can differentiate into keratinocyte-like cells. Stem cell therapies using allogeneic ASCs may be applicable to the treatment of RDEB and other skin diseases in near future.

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A homozygous insertion–deletion in the type VII collagen gene (COL7A1) in Hallopeau–Siemens dystrophic epidermolysis bullosa

Cited by 124 publications

References 43 publications

Keratinocyte-/Fibroblast-Targeted Rescue of Col7a1-Disrupted Mice and Generation of an Exact Dystrophic Epidermolysis Bullosa Model Using a Human COL7A1 Mutation

Keratinocyte-/Fibroblast-Targeted Rescue of Col7a1-Disrupted Mice and Generation of an Exact Dystrophic Epidermolysis Bullosa Model Using a Human COL7A1 Mutation

New insights into the immunoultrastructural organization of cutaneous basement membrane zone molecules

Adipose-Derived Stromal/Stem Cells for the Treatment of Skin Diseases

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