Keratin Intermediate Filament Fragility Module

Module keratin_intermediate_filament_fragility 5 disorders Pathograph 5

A conserved cytoskeletal-fragility module for the keratinopathies. Keratins assemble as obligate heterodimers of one type I and one type II chain into the intermediate filament network that gives a keratinocyte its mechanical resilience. A heterozygous missense or small in-frame variant in a filament-assembly domain is incorporated into that network and poisons it in trans, so a single mutant allele collapses the filament system - the defining dominant-negative mechanism of this disease group. The weakened keratinocyte lyses under mechanical stress that normal skin tolerates. Which tissue blisters is set not by the mechanism, which is identical throughout, but by where the affected keratin pair is expressed: basal K5/K14, suprabasal K1/K10, palmoplantar and appendageal K6/K16/K17, hair-shaft K81/K83/K86. Disorder entries reference these nodes via conforms_to and substitute the affected keratin pair.

⚙

Pathophysiology Nodes

5 shared nodes are defined in this module.

◉

Cell Types

⇄

Biological Processes

Notes

This is a shared mechanism module, not a disease. Disorder-specific substitutions at the trigger node, listed with the expression domain that sets the affected tissue: KRT5 / KRT14 in basal keratinocytes (epidermolysis bullosa simplex - intraepidermal basal cytolysis); KRT1 / KRT10 in suprabasal keratinocytes (epidermolytic ichthyosis, formerly epidermolytic hyperkeratosis, and the mosaic epidermal naevus form); KRT9 in palmoplantar suprabasal epidermis (epidermolytic palmoplantar keratoderma); KRT6A / KRT6B / KRT6C / KRT16 / KRT17 in nail bed, palmoplantar epidermis and pilosebaceous units (pachyonychia congenita); KRT81 / KRT83 / KRT86 in the hair shaft cortex (monilethrix); KRT3 / KRT12 in corneal epithelium (Meesmann corneal dystrophy). The mutational hot spots are the helix boundary motifs at the ends of the central rod domain (the beginning of 1A and the end of 2B) plus the H1 head domain, because those are the regions mediating end-to-end molecular overlap during filament assembly. A variant there is more disruptive, and more dominant, than one in the middle of the rod - which is why genotype maps onto severity within a single gene. Scope boundary with `dermal_epidermal_junction_adhesion_failure`. EBS reaches a plane of separation in skin, so it conforms to that module at its separation node, but its proximal lesion is intracellular and belongs here. Do not conform an EBS entry to that module's *trigger* node, which asserts a basement-membrane-zone attachment defect. PLEC/plectin is the genuine hinge: plectin links the keratin network into the hemidesmosome, so plectin-deficient EB has a real claim on both triggers. Scope boundary with `epidermal_cornification_failure`. Epidermolytic ichthyosis conforms to BOTH modules and to neither alone: the K1/K10 lesion is a keratin filament lesion (here), while the resulting hyperkeratotic scaling arises through the barrier-failure and compensatory-hyperproliferation chain of the cornification module. Curate both, rather than forcing one to carry the other. Not an Xogenesis module: the terminal output is cytolysis, the destruction of cells, not the formation of a pathological anatomical entity. Conformance requires evidence of keratin filament network disruption or keratinocyte cytolysis. A keratin gene expressed in the affected tissue, or a keratin variant of unknown consequence, does not conform on that basis alone; in particular a keratin *null* allele acting by haploinsufficiency is a different mechanism from the dominant-negative one this module models.

↗

Used By Disorder Entries

Epidermolysis Bullosa Simplex via KRT5/KRT14 Mutations Disrupt Keratin Intermediate Filament Network → Dominant-Negative Keratin Variant in a Filament Assembly Domain , Dominant-Negative Disruption of Filament Assembly → Keratin Filament Network Collapse and Aggregation , Mechanical Stress-Induced Keratinocyte Cytolysis → Keratinocyte Cytolysis Within the Keratin Expression Domain

Isolated Woolly Hair via KRT74 Hair-Shaft Keratin Filament Defect → Keratin Filament Network Collapse and Aggregation

KRT1 Keratinopathies via KRT1 Dominant-Negative Mutations → Dominant-Negative Keratin Variant in a Filament Assembly Domain , Tonofilament Clumping and Cytolysis → Keratin Filament Network Collapse and Aggregation

Monilethrix via Dominant-Negative Hair Cortex Keratin Variant → Dominant-Negative Keratin Variant in a Filament Assembly Domain , Cortical Keratin Network Collapse → Keratin Filament Network Collapse and Aggregation , Defective Keratin Assembly in the Hair Shaft Cortex → Loss of Keratinocyte Mechanical Resilience

Pachyonychia Congenita via Dominant-Negative Keratin Variant → Dominant-Negative Keratin Variant in a Filament Assembly Domain , Keratin Intermediate Filament Network Disruption → Keratin Filament Network Collapse and Aggregation , Loss of Keratinocyte Mechanical Resilience

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence-backed metadata.

⚙

Pathophysiology

Dominant-Negative Keratin Variant in a Filament Assembly Domain

trigger

A heterozygous missense or small in-frame insertion/deletion variant falls in a keratin domain required for filament assembly - characteristically a helix boundary motif at the start of the 1A or the end of the 2B rod segment, or the H1 head domain. These are the regions that mediate the end-to-end molecular overlaps between adjacent keratin molecules, so a substitution there yields a chain that still enters the filament but cannot support normal assembly.

keratinocyte CL:0000312

keratin filament GO:0045095

Used by disorders

Epidermolysis Bullosa Simplex as KRT5/KRT14 Mutations Disrupt Keratin Intermediate Filament Network

KRT1 Keratinopathies as KRT1 Dominant-Negative Mutations

Monilethrix as Dominant-Negative Hair Cortex Keratin Variant

Pachyonychia Congenita as Dominant-Negative Keratin Variant

Downstream

Keratin Filament Network Collapse and Aggregation The mutant chain is incorporated into the obligate heterodimer and disrupts assembly of the whole network in trans.

Keratin Filament Network Collapse and Aggregation

amplifier

Because keratin filaments are obligate heterodimers of a type I and a type II chain, mutant protein from a single allele is incorporated throughout the network rather than segregating from it. The filament system fails to form a normal cytoplasmic array and instead collapses into perinuclear clumps and tonofilament aggregates - the ultrastructural hallmark of this disease group, and the basis of the clumped tonofilaments seen in Dowling-Meara EBS.

keratinocyte CL:0000312

intermediate filament organization GO:0045109 ABNORMAL

keratin filament GO:0045095

Used by disorders

Epidermolysis Bullosa Simplex as Dominant-Negative Disruption of Filament Assembly

Isolated Woolly Hair as KRT74 Hair-Shaft Keratin Filament Defect

KRT1 Keratinopathies as Tonofilament Clumping and Cytolysis

Monilethrix as Cortical Keratin Network Collapse

Pachyonychia Congenita as Keratin Intermediate Filament Network Disruption

Downstream

Loss of Keratinocyte Mechanical Resilience A collapsed filament network no longer distributes mechanical load across the cell.

Loss of Keratinocyte Mechanical Resilience

central effector

The keratin network is the load-bearing element of the keratinocyte, so its collapse leaves the cell unable to withstand shear and compression. This is the rate-limiting, disorder-agnostic node of the module: every affected keratin pair converges here, and conformance should be declared against it.

keratinocyte CL:0000312

cellular response to mechanical stimulus GO:0071260 ABNORMAL

Used by disorders

Monilethrix as Defective Keratin Assembly in the Hair Shaft Cortex

Pachyonychia Congenita

Downstream

Keratinocyte Cytolysis Within the Keratin Expression Domain Mechanically incompetent cells rupture, and they do so in whichever epithelial layer or appendage expresses the affected keratin pair.

Keratinocyte Cytolysis Within the Keratin Expression Domain

effector

Cells lyse under mechanical stress, producing a plane of tissue disruption at the level where the affected keratin pair is expressed. This node is where the module's single mechanism becomes several distinct diseases: basal K5/K14 cytolysis splits the epidermis at its base and blisters; suprabasal K1/K10 cytolysis produces the vacuolar degeneration of epidermolytic ichthyosis; K6/K16/K17 involvement affects nail bed, palmoplantar epidermis and pilosebaceous units; hair-cortex keratins produce a fragile, beaded hair shaft.

basal keratinocyte CL:0002187

cytolysis GO:0019835 INCREASED

Used by disorders

Epidermolysis Bullosa Simplex as Mechanical Stress-Induced Keratinocyte Cytolysis

Downstream

Mechanically Provoked Blistering, Hyperkeratosis and Appendage Dystrophy Repeated cytolysis in the affected compartment produces the clinical phenotype characteristic of that keratin pair.

Mechanically Provoked Blistering, Hyperkeratosis and Appendage Dystrophy

consequence

The clinical endpoint, which varies with the expression domain but is uniformly provoked or worsened by friction and pressure: trauma-induced blistering favouring hands and feet; erythema and blistering in the neonate giving way to thick adherent hyperkeratosis; focal palmoplantar keratoderma with disabling plantar pain and hypertrophic nail dystrophy; or fragile beaded hair with patchy alopecia. Because the trigger is mechanical, disease burden tracks physical activity and heat, and management is largely protective.

keratinization GO:0031424 ABNORMAL