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) 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).
ConnexinSubfamilyGene name βββββαβββββα 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.
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.
GeneSyndromeDomain GJB2 GJB3 GJB4 GJB6 GJA1 KID Hypotrichosis-deafness Hystrix-like icthyosis-deafness PPK Bart-pumphrey Vohwinkles 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 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.
In older patients, papillomatous skin lesions that can progress to SCC % 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 EKV-like lesions, more pronounced mucositis leading to fungal superinfection.
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 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.
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.
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)
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 cell envelope protein loricrin resembling Vohwincles syndrome (Cx26) with icthyosis.
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 is required for epithelial mobilization.