Gap junction diseases of the skin

Report
By
Lamia Elgarhy
Assistant lecturer
Invertebrate
• Innexins
Vertebrates
• Connexins
Plants
• Pannexins
• Plasmodesmata

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.

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.

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.

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.

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).

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).

Transjunctional voltage.

Membrane voltage.

Phosphorylation.

pH.

Ca2+.

Channel composition.
Connexin
Subfamily
Gene name
26
β
GJB2
30
β
GJB6
30.3
β
GJB4
31
β
GJB3
31.1
β
GJB5
43
α
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.

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.

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.
Gene
Syndrome
Domain
GJB2
KID
NT,E1
Hypotrichosis-deafness
NT
Hystrix-like icthyosis-deafness
E1
PPK
E1,E2
Bart-pumphrey
E1
Vohwinkle’s
E1
Mucositis-deafness
TM3
EKV et progressiva
NT,TM1,TM3
GJB3
EKV et progressiva, erythema gyratum
NT,TM1,TM3,
GJB4
repens/Cram-Mevorah type
TM4
GJB6
Clouston
NT, TM1,E1
GJA1
ODDD with PPK
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.

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.
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.
(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).

Transiant hypotrichosis.

Mucositis.

Nail dystrophy.

Deafness.

Evolving
to
pronounced
EKV-like
mucositis
superinfection.
lesions,
leading
to
more
fungal

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.

Scaly crusted plaques on the scalp and
scaling of external auditory canals causing
obstruction were present.
One of the effects of
Cx26
mutations
reduced
is
incorporation
of other connexins into
the
cell
membrane
(transdominant
so
the
effect)
disease
phenotype is due not
much to Cx26 mutation
as
to
widespread
consequences for gap
junctional
communication.

Relatively
fixed
erythematous
patches
areas
of
with
hyperkeratosis
capriciously
and
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.

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
(transdominant effect)
by
Cx43

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

Some
cases
may
represent
loricrin
keratoderma caused by mutations in the
cornified
resembling
cell
envelope
Vohwincle’s
with icthyosis.
protein
loricrin
syndrome
(Cx26)

Hypotrichosis.

Nail dystrophy.

Palmoplanter
hyperkeratosis.

Teeth,
sweat
and
sebaceous glands are
not affected.

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

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
mobilization.
is
required
for
epithelial

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