This is a shared mechanism module, not a disease.
Disorder-specific substitutions at the trigger node, ordered by the cleavage plane each produces: PLEC (the plectin link from the keratin network into the hemidesmosome); ITGA6 / ITGB4 and COL17A1 (hemidesmosomal); LAMA3 / LAMB3 / LAMC2 (lamina lucida, the anchoring filament level); COL7A1 (sublamina densa, the anchoring fibril level); FERMT1 / kindlin-1 (mixed, and the reason Kindler EB shows more than one plane in the same biopsy).
KRT5 and KRT14 are deliberately NOT in that list even though they cause an EB subtype, because they are intracellular filament proteins rather than components of the extracellular attachment network this node asserts. See the scope boundary below.
Scope boundary with `keratin_intermediate_filament_fragility`. Epidermolysis bullosa simplex is classified as EB because it blisters, but its proximal lesion is dominant-negative collapse of the keratin network inside the basal keratinocyte, not loss of an extracellular attachment component. An EBS entry should conform to the keratin module, and should NOT conform to this module's trigger node.
It should not conform to this module's *separation* node either, and the reason is worth stating because it is easy to get wrong: EBS splits **intraepidermally**, through the cytolysing basal keratinocyte, above an intact basement membrane zone - not at the dermal-epidermal junction. The blister looks the same clinically and the plane is not the same. What EBS shares with this module is the keratin module's cytolysis node, which is where its separation belongs.
PLEC (plectin) is the genuine hinge and the one EBS-associated gene that does belong here, because plectin is a hemidesmosomal component linking the keratin network into the attachment complex; a plectin-deficient entry has a real claim on both this module's trigger and the keratin module's.
This module models the *inherited* attachment defect. The acquired autoantibody-mediated route to the same cleavage planes (epidermolysis bullosa acquisita, bullous pemphigoid, anti-laminin-332 mucous membrane pemphigoid) reaches the separation node through immune targeting of the same proteins; such an entry may conform at the separation node while curating its own autoimmune trigger.
Not an Xogenesis module: the blister is a plane of tissue separation - a failure of an adhesive structure - not the formation of a new pathological anatomical entity.
Conformance requires evidence of mechanically-provoked separation at the dermal-epidermal junction. A gene expressed at the basement membrane zone, or a disorder with skin fragility from a different cause (cornification defects, desmosomal acantholysis), does not conform on that basis alone.
Basement Membrane Zone Attachment Component Defect
trigger
A structural component of the interconnected hemidesmosome - anchoring filament - anchoring fibril network of the cutaneous basement membrane zone is absent, reduced, or structurally abnormal. The network spans from the keratin cytoskeleton of the basal keratinocyte, across the lamina lucida and lamina densa, into the papillary dermis, and each disorder removes one link from it.
Downstream
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Loss of Adhesive Integrity at a Defined Cleavage Plane
Removing one link leaves the network mechanically incompetent at the exact level that link occupies.
Show evidence (2 references)
"Cutaneous basement membrane zone (BMZ) consists of a number of attachment structures that are critical for stable association of the epidermis to the underlying dermis. These include hemidesmosomes, anchoring filaments and anchoring fibrils which form an interconnecting network extending from..."
Defines the attachment network whose components are the substitutable triggers of this module.
"The NC-1 domains are believed to interact with components of the basement membrane and thus to mediate the attachment of the basement membrane to the dermis."
Gives the molecular function of the deepest link in the network, type VII collagen in anchoring fibrils, which the dystrophic forms lose.
Loss of Adhesive Integrity at a Defined Cleavage Plane
amplifier
The attachment network loses tensile competence at one specific ultrastructural level - within the basal keratinocyte, at the hemidesmosome, within the lamina lucida, or beneath the lamina densa - determined by where the missing component sits. This level-specificity is the organizing principle of EB classification: the same clinical sign (a blister) arising at different depths defines the simplex, junctional, and dystrophic categories, and predicts whether healing will be scarless or scarring.
Downstream
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Mechanically Induced Dermal-Epidermal Separation and Blistering
An adhesively incompetent plane separates under shear forces that intact skin tolerates without injury.
Show evidence (2 references)
"Based on constellations of the phenotypic manifestations, severity of the disease, and the level of tissue separation within the cutaneous BMZ, EB has been divided into clinically distinct subcategories, including the simplex, hemidesmosomal, junctional and dystrophic variants."
States that the level of separation within the basement membrane zone is what partitions EB into subtypes, which is the claim this node makes.
"H-JEB is caused by loss-of-function mutations in LAMA3, LAMB3, or LAMC2, leading to complete loss of laminin 332, the major component of anchoring filaments, which mediate epidermal-dermal adherence."
Worked example of one plane: loss of the anchoring filament component laminin 332 removes epidermal-dermal adherence at the lamina lucida.
Mechanically Induced Dermal-Epidermal Separation and Blistering
central effector
Ordinary mechanical shear - friction, pressure, minor trauma - separates the tissue at the incompetent plane, and fluid accumulates in the resulting cleft to form a blister or erosion. This is the rate-limiting, disorder-agnostic node of the module: every attachment-component lesion converges here, and it is the node against which conformance should be declared.
Downstream
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Chronic Erosion, Impaired Healing and Dermal Scarring
Blisters rupture into erosions; repeated cycles of injury and repair at a plane below the lamina densa heal with scarring rather than restitution.
Show evidence (2 references)
"Aberrations in this network structure, e.g. due to genetic lesions in the corresponding genes, can result in fragility of the skin at the level of the cutaneous BMZ."
States the amplifier-to-central-effector step: network aberration yields skin fragility at the basement membrane zone.
"Dystrophic epidermolysis bullosa (DEB) is characterized by skin fragility manifested by blistering and erosions with minimal trauma."
Documents the defining feature of this node - blistering provoked by minimal mechanical trauma - in the sublamina densa form.
Chronic Erosion, Impaired Healing and Dermal Scarring
effector
Ruptured blisters leave chronic, slowly healing erosions and wounds. Where the plane of separation lies beneath the lamina densa, healing is fibrotic rather than restitutive, producing milia, atrophic scarring, and progressive contracture. The persistently wounded, inflamed, and fibrotic dermal microenvironment is itself the substrate for the malignant complication. Forms that split above the lamina densa heal without scarring, so this node is reached to markedly different degrees across conforming disorders.
Downstream
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Cutaneous and Extracutaneous Complications of Skin Fragility
Chronic wounding and fibrosis produce the organ-level burden of disease, including squamous cell carcinoma at chronically wounded sites.
Show evidence (2 references)
"Clinical findings in severe RDEB include skin fragility manifested by blistering and erosions with minimal trauma that heals with milia and scarring."
Documents the scarring rather than restitutive healing that follows separation below the lamina densa.
"A recent discovery of a remarkably distinct tumour microenvironment in part explains the aggressive nature of RDEB SCC and the importance of collagen VII expression as a potential therapeutic measure."
Links the chronically wounded, collagen-VII-deficient dermal microenvironment of this node to the malignant consequence downstream.
Cutaneous and Extracutaneous Complications of Skin Fragility
consequence
The organ-level endpoint. Because the same attachment network operates in every stratified squamous epithelium, fragility is not confined to skin: nail dystrophy, oral and oesophageal erosion with stricture, corneal erosion, and dental enamel defects occur depending on which component is lost. In the sublamina densa forms, cutaneous squamous cell carcinoma arising in chronically wounded skin becomes the leading cause of death in adulthood, and it is not UV-driven.
Show evidence (2 references)
"Patients with RDEB have up to a 50 fold increased incidence of cutaneous squamous cell carcinoma (cSCC) which is independent of ultraviolet (UV) exposure."
Quantifies the malignant consequence and establishes that it follows from the chronic wounding of this module rather than from UV mutagenesis.
"In spite of this progress, squamous cell carcinoma (SCC) is still a major cause of morbidity and mortality, particularly in Hallopeau--Siemens recessive dystrophic EB."
Establishes that this consequence node, not the blistering itself, carries the mortality burden in the severe recessive dystrophic form.