This document discusses the structure and function of desmosomes, which are the major cellular structures that maintain cell-cell adhesion in the epidermis. Desmosomes are composed of three major protein families: plakins (including desmoplakin), armadillo proteins, and desmosomal cadherins. Desmoplakin links the desmosomal cadherins to the keratin intermediate filaments inside the cell. Mutations in desmosomal proteins can cause skin fragility disorders and cardiomyopathies. The document also briefly summarizes other epidermal junctional complexes including adherens junctions, tight junctions, and gap junctions.

1. Jai Kumar Pillai
KIMS, Bangalore
1
DESMOSOMES

2. EPIDERMAL ADHESION
 Epidermal integrity is required for protection
against mechanical , physical & microbial insults
 The major cellular structures involved in
maintaining this cell-cell adhesion are the
desmosomes
2

3. Other epidermal attachment
complexes
 Adherens junction
 Tight junction
 Gap junction
3

4. DESMOSOMES
 Macula Adherens
 Intercellular bridges
 Major cell adhesion jn of epidermis
 Anchor apposing keratinocyte cell membranes
to intracellular KIF
 Location – all epithelial tissues , myocardium &
cortex of LN
4

5. 5

6. C/S: symmetric, consists of 2 apposing
dense plaques inside membranes
Intercellular centre-Desmoglea, 30nm
Thin electron dense midline in centre(formed
by amino terminus of desmosomal cadherins)
Inner dense plaque & outer dense plaque
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ULTRASTRUCTURE

7. 7

8. Biochemical Characterisation
3 Major Gene Families
Plakins ( desmoplakin )
Armadillo proteins( plakoglobins & plakophilins)
Desmosomal cadherins( desmogleins & desmocollins)
Additional proteins- perp, ninein, kazrin &
corneodesmosin8

9. Outer dense plaque
 10-20nm from plasma
membrane
 Contains desmosomal
cadherins cytoplasmic tails,
plakoglobin, plakophilin, amino
terminus of desmoplakin
Inner dense plaque
 40-50nm from PM
 Carboxy terminus of
desmoplakin interacting with
KIF
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10. DESMOPLAKIN
 Major inner plaque component
 Exists as 1 & 2
 Family includes
BPAG1, Plectin
plaque proteins of HD
envoplakin & periplakin
10

11.  Modular protein
 Rod like centre
 C terminus binds to KF , Amino terminus binds to
plakoglobin
 Major link b/w KIF & desmosomal plaque
 Also play role in development of epithelium
11

12. APPLIED ASPECT
Mutations causes
 PPK(striate or diffuse)
 Dilated cardiomyopathy
 Wooly hair
 Skin blisters
Haploinsufficiency
 AD striate PPK
12

13. Non-sense mutation affecting
desmoplakin1
 Naxos like syndrome-
PPK, Wooly hair & ARVC
Compound heterozygous mutation
 Lethal acantholytic epidermolysis
bullosa
widespread epidermolysis
generalized alopecia
anonychia
neonatal teeth
Total skin denudement
Absent toe nails
Total alopecia
Single row of
BK13

14. PLAKOGLOBIN
 γ-catenin
 2nd major protein in desmosomal
plaques
 Ubiquitously present in all epithelia
 Can also localise to nucleus & modulate
gene transcription
 Link between desmogleins &
desmocollin to desmoplakins
14

15. APPLIED
ASPECT
Plakoglobin mutation
result in NAXOS
disease
 Diffuse PPK
 Wooly hair
 ARVC
15

16. PLAKOPHILIN
 Binds to desmoplakin & desmosomal cadherins
 Aids in clustering & stability of plaque
 Localise to nucleus where it regulates translation &
cell proliferation
16

17. APPLIED ASPECT
Plakophilin1- mutation causes Ectodermal dysplasia
skin fragility syndrome
Sparse hair, skin
erosions Perioral erosions Intraepidermal clefting
17

18.  Plakophilin2- mutation are mcc of AD
arrythmogenic RV cardiomyopathy
18

19. DESMOSOMAL CADHERINS
 link between the intracellular
plaque &
the extracellular desmoglea
 Ca2+ dependent adhesion
 Desmogleins-4
isoforms(1,2,3,4)
 Desmocollins 3 isoforms-1,2,3
 Key role in initiating
desmosomal assembly19

20.  Desmoglein 1 & 3 – predominant in epidermis &
mucous membranes, thymic epithelial cells
 Dsg2- major isoform in most simple & transitional
epithelia , cardiac myocytes
 Dsg4- more in hair follicle, testes & prostate
 Dsg3- expressed in SCC, molecular target for
therapy
20

21. DESMOCOLLINS
3 isoforms-1,2,3
 Dsc 3- expressed in stratified squamous
epithelia of skin & oropharynx
 Dsc2-only isoform present in cardiac tissue
21

22. Mechanism of intercellular
adhesion
 Amino terminal tryptophan of 1
cadherin molecule
 Interacts with a hydrophobic acceptor
of another cadherin molecule in
adjacent cells
 Forms trans-adhesive interphase
 Interactions are homophilic(Dsg-Dsg) &
heterophilic(Dsg-Dsc)22

23. Applied Aspects
Dsg1-target of proteolytic cleavage in
 Bullous Impetigo
 SSSS
 Inherited Icthyosis a/w Netherton syndrome
23

24.  SSSS- cleavage of Dsg1 by staphylococcal
exfoliative toxin , occurs between extracellular
domains 3&4
Extensive areas
of desquamation
Perioral crusting, fissuring
24

25. Pathogenic antibodies to Dsg1
 Pemphigus foliaceus
 MC pemphigus vulgaris
 Paraneoplastic pemphigus
25

26.  AD mutations causing Haploinsufficiency of Dsg1-
--Palmoplantar Keratoderma
26

27. DESMOGLEIN 2 & DESMOCOLLIN
2
 Implicated in CVD as a cause of AD arrythmogenic
RV cardiomyopathy
27

28. DESMOGLEIN 3
Target of autoabs in
 Mucosal & MC pemphigus vulgaris
 Paraneoplastic pemphigus
Target-Amino terminal extracellular
domains of Dsg3
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29. DESMOGLEIN 4 & DESMOCOLLIN 3
Mutations lead to
 AR forms of hypotrichosis & monilethrix
Beaded appearance of hair
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30. DESMOCOLLIN 1
 Target of autoAbs in Subcorneal Pustular
Dermatosis of IgA Pemphigus
Flacid pustules, erythematous skin
Circinate pattern
Neutrophil infiltrate
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31. Desmoglein Compensation
Theory
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Dsg3 compensates
for Dsg1
Dsg3>Dsg1
Dsg1
compensates
for Dsg3
Low Dsg1

32. OTHER DESMOSOMAL
PROTEINS
Envoplakin & Periplakin
 Expressed in superficial layer of epidermis
 Incorporate into corneodesmosomes of SC
 Paraneoplastic pemphigus: Autoantibodies to these
proteins are characteristic
32

33. Corneodesmosin
 Secreted gp
 Incorporates into corneodesmosomes
 Expressed in inner root sheath of hair follicle
Mutation
AD hypotrichosis simplex of scalp
Scalp biopsy- loss of cohesion in inner root sheath &
aggregates of corneodesmosin around hair follicle
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34. FUNCTIONS
 Major- cell adhesion
 Development & differentiation of epidermis
 May mediate signal transduction( armadillo family B-
catenin, plakophilins)
 B-catenin—wnt signaling pathway
Translocates to nucleus to form a transcription
factor
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35. ADHERENS JUNCTION
 Electron dense , transmembrane
structures, engage with actin
skeleton
 Functions
epithelial assembly, barrier
formation
cell motility, changes in cell
shape
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36. U/S: characterised by 2 opposing membranes
 Seperated by gap of 20nm & 0.2-0.5um in diam
 Comprises of 2 basic adhesive units
nectin–afadin complex and the classical cadherin
complex
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37. 37

38.  Cadherins form a complex with the catenins (α-,
β-, and p120 catenin) & help mediate adhesion and
signalling
 Nectins form a structural link to the actin
cytoskeleton via afadin (AF-6)
38

39. Applied Aspects
 P-cadherin(CDH3) mutations result in AR
hypotrichosis with juvenile macular dystrophy
39

40. TIGHT JUNCTIONS
 Zonula occludens
 Major regulators of
permeability in epithelia
 Skin barrier integrity &
maintaining cell polarity
 Function: regulate the
paracellular flux of water-
soluble molecules between
adjacent cells
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41.  Structural components-
 Claudin(24 subtypes)—main is 1&4
 IgG-like family of junctional adhesion molecules
(JAMs)
 Occludin
 claudins and occludins can bind to the intracellular
zonula occudens proteins ZO-1, ZO-2, ZO-3
 Can interact with actin-direct link with cytoskeleton
41

42. 42

43.  Tight jn , adherens jn & desmosomes form the
apical junctional complex in ep cells
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44. Applied Aspects
 Claudin 1 –AR diffuse ichthyosis with large scales,
hypotrichosis, scarring alopecia & sclerosing
cholangitis
 claudin 16(paracellin-1)-familial hypomagnesaemia
with hypercalciuria and nephrocalcinosis
 claudin 14 - AR deafness disorder
 ZO-2 - familial hypercholanaemia
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45. GAP JUNCTIONS
 Comprise clusters of intercellular channels, known as
connexons
 1 connexon formed by assembly of 6 connexin subunits
within Golgi
 At PM, adjacent connexons associate to from Gap
junction
 Stability of Gap jn regulated by PKC, Src kinase, Ca2+,
calmodulin and pH
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46.  Connexins (α, β and γ) – forms homotypic or
heterotypic connnexons
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47. Functions
 Sharing low-molecular-mass metabolites (<1000 Da) &
ion exchange between neighbouring cells
 cell synchronization, differentiation, cell growth and
metabolic coordination of avascular organs, including
epidermis.
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48. APPLIED ASPECT
Mutations
Cx26-
Bart pumphrey syndr
Palmoplantar keratoderma with
deafness
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49.  30- Cloustons syndrome
Atrichia of scalp
nail dystrophy
diffuse plantar
keratoderma
 30.3 & 31
Erythrokeratoderma
variabilis
Oval red scaly plaques-joind-map like49

50. REFERENCES
 ROOKS 8th edition
 FITZPATRICKS 8th edition
 BOLOGNIA 3rd edition
 IADVL 4th edition
 LEVER’S histopathology 10th edition
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51. THANK YOU
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