Gap junction diseases of the skin

By Lamia Elgarhy

Assistant lecturer

•Innexins

Invertebrate •Con

nexins

•Pannexins

Vertebrates

•Plasmodesmata

Plants

Gap junctions

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.

INTRODUCTION

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.

Pannexins of the skin

They are transmembrane proteins that can

form intercellular channels, gap junctions.

They are widely expressed in several tissues

including the skin.

Connexins are named according to their

molecular weight in kilodaltons.

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.

Connexins

They consist of:

1. an amino terminal (N-terminal).

2. 4 transmembrane parts (TM1-4).

3. Two extracellular loops (E1-E2).

4. One intracytoplasmic loop.

5. Cytoplasmic carboxyl terminal (C-

terminus).

Connexin proteins

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).

Connexins

Transjunctional voltage.

Membrane voltage.

Phosphorylation.

pH.

Ca2+.

Channel composition.

Factors regulating channel permeability

Human connexins associated with epidermal disorders

Connexin Subfamily Gene name

26

30

30.3

31

31.1

43

β

β

β

β

β

α

GJB2

GJB6

GJB4

GJB3

GJB5

GJA1

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.

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.

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.

Connexins

Skin expressed connexin mutations and their associated

inherited disordersGene Syndrome Domain

GJB2

GJB3

GJB4

GJB6

GJA1

KID

Hypotrichosis-deafness

Hystrix-like icthyosis-deafness

PPK

Bart-pumphrey

Vohwinkle’s

Mucositis-deafness

EKV et progressiva

EKV et progressiva, erythema gyratum

repens/Cram-Mevorah type

Clouston

ODDD with PPK

NT,E1

NT

E1

E1,E2

E1

E1

TM3

NT,TM1,TM3

NT,TM1,TM3,

TM4

NT, TM1,E1

CT

100 reported cases.

Cobblestone or shark skin like

hyperkeratosis on extremeties

and face.

Profound sensoryneural deafness

Alopecia

Vascularizing keratitis

Mucosal involvement is not

typical.

GJB2(Cx26)KID S SYNDROME

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.

KID S SYNDROME

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.

PPK- deafness group

(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.

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).

PPK- deafness groupVohwinkle’s syndrome

Vohwinkle’s syndrome

Vohwinkle’s syndrome

Transiant hypotrichosis.

Mucositis.

Nail dystrophy.

Deafness.

Evolving to EKV-like lesions, more

pronounced mucositis leading to fungal

superinfection.

Hypotrichosis-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 syndrome

Scaly crusted plaques on the scalp and

scaling of external auditory canals causing

obstruction were present.

Mucositis-deafness syndrome

One of the effects of Cx26 mutations is reduced incorporation of other connexins into the cell membrane (transdominant effect) so the disease phenotype is due not much to Cx26 mutation as to widespread consequences for gap junctional communication.

MESSAGE

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.

GJB3 (Cx31)EKV et progressiva

EKV et progressiva

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)

Progressive symmetric erythrokeratoderma (PSEK) OF

Gottron

It is identical to GJB3 but less severe.

In some mutations, erythema gyratum

repens 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 type

Some cases may represent loricrin

keratoderma caused by mutations in the

cornified cell envelope protein loricrin

resembling Vohwincle’s syndrome (Cx26)

with icthyosis.

GJB4 (Cx30.3) EKV et progressiva, erythema gyratum repens/Cram-Mevorah

type

Hypotrichosis.

Nail dystrophy.

Palmoplanter

hyperkeratosis.

Teeth, sweat and

sebaceous glands are

not affected.

GJB6 (Cx30)Clouston syndrome (Hidrotic

ectodermal dysplasia

Eye abnormalities.

Hypotelorism.

Hypoplasia of the ala nasi.

Prominent defects of the acral skeleton:

typeIII syndactyly, clinodactyly and hypoplasia of

the middle phalanx of the fifth digits.

White matter defects causing spastic paraplegia

and urinary incontinence

GJA1(Cx43)ODDD

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.

GJA1(Cx43)