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Gap junction diseases of the skin. By Lamia Elgarhy Assistant lecturer. Gap junctions. INTRODUCTION. Gap junctions are small membrane pores that facilitate rapid intercellular communication in all vertebrate cells, and are composed of connexins .

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Gap junction diseases of the skin

Gap junction diseases of the skin

By

Lamia Elgarhy

Assistant lecturer



Introduction
INTRODUCTION

  • Gap junctions are small membrane pores that facilitate rapid intercellular communication in all vertebrate cells, and are composed of connexins.

  • In humans, there are 21 different connexin genes are expressed.

  • Mutations lead to ectodermal dysplasia.


Pannexins of the skin
Pannexins of the skin

  • P1 and P3 are expressed in the skin. They are important in epidermal differentiation.

  • They can form gap junctions and hemichannels, similar to connexins.

  • To date, no disease states are associated with pannexin mutations.


Connexins
Connexins

  • They are transmembrane proteins that can form intercellular channels, gap junctions. They are widely expressed in several tissues including the skin.

  • Connexinsare named according to their molecular weight in kilodaltons.


Connexins1
Connexins

  • Their genes are named according to their sequence. There are 5 subfamilies as follows:

    α(GJA), β(GJB), Υ(GJC), δ(GJD), ε(GJE).

    Connexon or hemichannel is composed of 6 connexins. It is homomeric if they are of one connexin type and heteromeric if more than one.


Connexin proteins
Connexin proteins

  • They consist of:

  • an amino terminal (N-terminal).

  • 4 transmembrane parts (TM1-4).

  • Two extracellular loops (E1-E2).

  • One intracytoplasmic loop.

  • Cytoplasmic carboxyl terminal (C-terminus).


Connexins2
Connexins

  • A connexon in the cell membrane will dock with another one in a neighboring cell and form a gap junction channel. It is visualized as a tube with a watery interior that permits the passage of water and small messenger molecules (>1kDa).


Factors regulating channel permeability
Factors regulating channel permeability

  • Transjunctional voltage.

  • Membrane voltage.

  • Phosphorylation.

  • pH.

  • Ca2+.

  • Channel composition.


Human connexins associated with epidermal disorders
Human connexins associated with epidermal disorders


Connexins3
Connexins

  • N-terminus of Cx26 is important for voltage gating which is the regulation of channel permeability by membrane polarization by forming a funnel by its 6 helices.

  • Large C-terminal domain of Cx43 regulates channel permeability by ball and chain model.


Connexins4
Connexins

  • E1 domain is of crucial importance for gap junction function. Several mutations can lead to several pathogenic conditions.

  • Recently E2 mutation was discovered to cause PPK which was the same as the E1 mutation of PPK.


Connexins5
Connexins

  • Cx26 mutation is known to be recessive and cause deafness alone. While Cx31,Cx30.3 mutations are dominant and cause skin diseases.

  • Changes in gap junction communication are associated with hyperproliferative disorders such as psoriasis, SCC and delayed wound healing in diabetic skin.


Skin expressed connexin mutations and their associated inherited disorders
Skin expressed connexin mutations and their associated inherited disorders


Gjb2 cx26 kid s syndrome
GJB2(Cx26)KID S SYNDROME

  • 100 reported cases.

  • Cobblestone or shark skin like hyperkeratosis on extremeties and face.

  • Profound sensoryneural deafness

  • Alopecia

  • Vascularizingkeratitis

  • Mucosal involvement is not typical.



Kid s syndrome1
KID S SYNDROME

  • In older patients, papillomatous skin lesions that can progress to SCC.

  • 11-29% of all patients develop SCC.

  • KID syndrome propably results from both disturbed gap junction intercellular communication and possibly the presence of leaky channels.


Ppk deafness group
PPK- deafness group

All PPK- deafness mutations seem to cluster in E1 and E2 which have some role in channel assembly and /or transport.

Bart- Pumphrey syndrome:

  • Leuconychia

  • Knuckle pads are no more typical.

  • PPK is not usually very impressive.


Gap junction diseases of the skin

(H&E stain) shows compact orthokeratotic hyperkeratosis, hypergranulosis, and acanthosis of the epidermis. (f) Transmission electron micrograph demonstrating a normal-appearing gap junction plaque between granular keratinocytes.


Ppk deafness group vohwinkle s syndrome
PPK- deafness groupVohwinkle’s syndrome

  • Starfish or honey comb like keratoderma.

  • Constricting bands encircle the fingers and toes near the joints with resorption of underlying bones leading to falling off of digits (pseudo-ainhum).


Vohwinkle s syndrome
Vohwinkle’s syndrome


Vohwinkle s syndrome1
Vohwinkle’s syndrome


Hypotrichosis deafness syndrome
Hypotrichosis-deafness syndrome

  • Transianthypotrichosis.

  • Mucositis.

  • Nail dystrophy.

  • Deafness.

  • Evolving to EKV-like lesions, more pronounced mucositis leading to fungal superinfection.


Mucositis deafness syndrome
Mucositis-deafness syndrome

  • Severe mucositis of the mouth and anus.

  • Hearing impairment.

  • Dental cysts.

  • No PPK.

  • Scaly erythematous plaques on the face trunk and extremeties.

  • Excessive granulation tissue around gastrostomy and perianal skin.


Mucositis deafness syndrome1
Mucositis-deafness syndrome

  • Scaly crusted plaques on the scalp and scaling of external auditory canals causing obstruction were present.



Gjb3 cx31 ekv et progressiva
GJB3 (Cx31)EKV et progressiva

  • Relatively fixed patches of hyperkeratosis and erythematous areas with capriciously formed outlines, like the boundaries of seacoasts on maps.

  • erythematous areas move from hour to hour.

  • Lesions affect the face, buttocks and extensor surfaces of limbs.

  • PPK in half of cases.

  • Hair, nail and teeth are not affected.


Ekv et progressiva
EKV et progressiva


Progressive symmetric erythrokeratoderma psek of gottron
Progressive symmetric erythrokeratoderma (PSEK) OF Gottron

  • The same as EKV with absent migratory patches.

  • Recent data showed decreased expression of Cx31 and upregulated expression of Cx43 in hyper keratotic plaques of EKV patients, suggesting compensation by Cx43 (transdominant effect)


Gjb4 cx30 3 ekv et progressiva erythema gyratum repens cram mevorah type
GJB4 (Cx30.3) EKV et progressiva, erythemagyratumrepens/Cram-Mevorah type

  • It is identical to GJB3 but less severe.

  • In some mutations, erythemagyratumrepens like lesions.

  • Connexins 30.3 and 31 strongly interact and thus, it is assumed that mutations in the former affect gap junctional communication in a manner


Gjb4 cx30 3 ekv et progressiva erythema gyratum repens cram mevorah type1
GJB4 (Cx30.3) EKV et progressiva, erythemagyratumrepens/Cram-Mevorah type

  • Some cases may represent loricrinkeratodermacaused by mutations in the cornified cell envelope protein loricrin resembling Vohwincle’s syndrome (Cx26) with icthyosis.


Gjb6 cx30 clouston syndrome hidrotic ectodermal dysplasia
GJB6 (Cx30)Clouston syndrome (Hidroticectodermal dysplasia

  • Hypotrichosis.

  • Nail dystrophy.

  • Palmoplanter hyperkeratosis.

  • Teeth, sweat and sebaceous glands are not affected.


Gja1 cx43 oddd
GJA1(Cx43)ODDD

  • Eye abnormalities.

  • Hypotelorism.

  • Hypoplasia of the ala nasi.

  • Prominent defects of the acral skeleton:

    typeIIIsyndactyly, clinodactyly and hypoplasia of the middle phalanx of the fifth digits.

  • White matter defects causing spastic paraplegia and urinary incontinence


Gja1 cx43
GJA1(Cx43)

  • Blocking Cx43 expression using antisense RNA can accelerate healing of chronic wounds and that a peptide targted to the carboxyl-terminal tail can enhance wound closure rates.

  • Indeed , decreased junctional coupling, rather than connexin protein expression in epidermal keratinocytes is required for epithelial mobilization.