This is a shared mechanism module, not a disease.
Three substitutable routes into the trigger node, which are NOT interchangeable and should be curated as the specific route the disorder takes:
1. Structural gene loss - DSP (Carvajal syndrome, striate palmoplantar
keratoderma, arrhythmogenic cardiomyopathy), JUP/plakoglobin (Naxos
disease), DSG1 (striate palmoplantar keratoderma type 1, SAM syndrome),
PKP1 (ectodermal dysplasia-skin fragility syndrome), PKP2 and DSC2 and
DSG2 (arrhythmogenic right ventricular cardiomyopathy).
2. Autoantibody blockade - IgG against the DSG3 and/or DSG1 ectodomain in
pemphigus vulgaris and pemphigus foliaceus. The target protein is the same
as in route 1; only the mechanism of its removal differs, which is why an
acquired disease conforms to a module otherwise populated by Mendelian
entries.
3. Calcium-handling failure - ATP2A2/SERCA2 (Darier disease) and
ATP2C1/SPCA1 (Hailey-Hailey disease). These are not desmosomal proteins;
they are the ER and Golgi calcium pumps whose activity the post-translational
processing and assembly of desmosomal proteins depends on, so the desmosomal
defect here is secondary. Curate the calcium lesion as the trigger and the
desmosomal consequence downstream of it - do not assert a primary
desmosomal protein defect in Darier or Hailey-Hailey disease.
Dose-sensitivity is a real and curatable feature of route 1: DSP haploinsufficiency alone is sufficient for striate palmoplantar keratoderma, whereas the cardiocutaneous syndromes generally require a more severe or recessive allele. A conforming entry should preserve that distinction rather than describing every desmosomal lesion as equivalent.
Scope boundary with `keratin_intermediate_filament_fragility`. Both modules end in a mechanically fragile keratinocyte, but the failing element differs: there the filament network itself collapses, here the network is intact and its anchorage to the junction is lost. A DSP entry belongs here; a KRT5 entry does not.
Scope boundary with `cardiomyopathy_maladaptive_remodeling`. The cardiocutaneous entries reach ventricular remodeling and should keep conforming to that module for the heart-failure arm; this module supplies the upstream adhesion lesion that module takes as given.
Not an Xogenesis module: acantholysis is the dissolution of intercellular adhesion, not the formation of a pathological anatomical entity.
Conformance requires evidence of lost desmosomal adhesion - acantholysis, reduced or malformed desmosomes, or intermediate filament retraction from the plaque. Expression of a desmosomal gene in the affected tissue is not sufficient.
Desmosomal Component Loss or Blockade
trigger
A structural component of the desmosome becomes unavailable to the junction. It may be absent because the gene encoding it carries a loss-of-function variant, functionally blocked because autoantibody has bound its adhesive ectodomain, or unable to be assembled because the calcium compartmentalization required for its processing has failed.
Used by disorders
Darier Disease
as ATP2A2 Haploinsufficiency and Loss of SERCA2 Pump Activity
Downstream
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Failure of Desmosome Assembly and Intermediate Filament Anchorage
Without an available component, desmosomes are reduced in number or size and the intermediate filament network is no longer tethered to the plaque.
Show evidence (2 references)
"The identified mutation, resulting in a null allele and haploinsufficiency, was observed in genomic DNA from a kindred with the dominantly inherited skin disorder, striate palmoplantar keratoderma."
Documents the structural-gene route, and specifically that reduced dosage of one desmosomal plaque protein is by itself sufficient to cause disease.
"This study demonstrates that defects in ATP2C1 cause HHD and together with the recent identification of ATP2A2 as the defective gene in Darier's disease, provide further evidence of the critical role of Ca(2+)signaling in maintaining epidermal integrity."
Documents the calcium-handling route into this module and establishes that the two calcium pumps converge on the same epidermal-integrity endpoint.
Loss of Desmosomal Intercellular Adhesion
central effector
Adjacent cells lose the high-tensile adhesion desmosomes provide. This is the rate-limiting, disorder-agnostic node of the module: the structural, autoimmune, and calcium-handling routes all converge here, and conformance should be declared against it.
Downstream
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Acantholysis and Mechanical Failure of Desmosome-Dependent Tissues
Cells separate from their neighbours under the mechanical load their tissue normally carries.
Show evidence (2 references)
"This protein is a key component of desmosomes and adherens junctions, and is important for the tight adhesion of many cell types, including those in the heart and skin."
States the adhesive function lost at this node and, critically for this module, that the same junction serves both heart and skin.
"Antibody (Ab) binding interferes with the adhesive function of these molecules, leading to detachment and subsequently blister formation."
Shows the autoantibody route reaching this same node, supporting the claim that the acquired and inherited diseases share a convergence point.
Acantholysis and Mechanical Failure of Desmosome-Dependent Tissues
effector
Cells detach from one another in whichever desmosome-dependent tissue is affected. In epidermis this is acantholysis - suprabasal separation producing blisters, erosions, or the acantholytic dyskeratosis of Darier disease - and the palmoplantar epidermis, which bears the greatest shear, responds with keratoderma. In the hair shaft it yields a structurally abnormal woolly or fragile hair. In myocardium, myocyte detachment at the intercalated disc permits cell death and fibrofatty replacement, the substrate for arrhythmogenic cardiomyopathy.
Downstream
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Cutaneous, Appendageal and Cardiac Manifestations
Tissue-level adhesion failure produces the organ-level syndrome, whose composition depends on where the affected component is expressed.
Show evidence (2 references)
"Darier disease (DD) is an autosomal-dominant skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization."
Documents the epidermal instance of this node, reached through the calcium-handling route.
"Hailey-Hailey disease (HHD) is an autosomal dominant skin disorder characterized by suprabasal cell separation (acantholysis) of the epidermis."
Documents the same epidermal endpoint through the second calcium pump, supporting the convergence rather than a gene-specific effect.
Cutaneous, Appendageal and Cardiac Manifestations
consequence
The organ-level endpoint. Cutaneously this ranges from focal or striate palmoplantar keratoderma through generalized acantholytic blistering; the hair may be woolly or fragile; and where the affected component is also expressed in myocardium the syndrome includes cardiomyopathy with ventricular arrhythmia and a risk of sudden death that can substantially precede any cardiac symptom. The cardiac arm is the reason a dermatological diagnosis in this group carries a cardiological obligation.
Show evidence (2 references)
"Here, we describe the first recessive human mutation, 7901delG, in the desmoplakin gene which causes a generalized striate keratoderma particularly affecting the palmoplantar epidermis, woolly hair and a dilated left ventricular cardiomyopathy."
Documents the full three-organ cardiocutaneous endpoint arising from a single desmosomal lesion.
"A number of the patients with this syndromic disorder suffer heart failure in their teenage years, resulting in early morbidity."
Establishes that the cardiac arm, not the cutaneous one, carries the morbidity burden, which is why conforming entries must not treat the skin findings as the whole disease.