Gap junction diseases of the skin

1. Gap junction diseases of the skin By Lamia Elgarhy Assistant lecturer

2. Gap junctions

3. 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.

4. 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.

5. 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.

6. 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.

8. 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).

10. 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).

12. Factors regulating channel permeability • Transjunctional voltage. • Membrane voltage. • Phosphorylation. • pH. • Ca2+. • Channel composition.

13. Human connexins associated with epidermal disorders

14. 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.

15. 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.

16. 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.

17. Skin expressed connexin mutations and their associated inherited disorders

18. 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.

19. KID S SYNDROME

20. 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.

21. 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.

22. (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.

23. 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).

24. Vohwinkle’s syndrome

25. Vohwinkle’s syndrome

26. Hypotrichosis-deafness syndrome • Transianthypotrichosis. • Mucositis. • Nail dystrophy. • Deafness. • Evolving to EKV-like lesions, more pronounced mucositis leading to fungal superinfection.

27. 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.

28. Mucositis-deafness syndrome • Scaly crusted plaques on the scalp and scaling of external auditory canals causing obstruction were present.

29. MESSAGE

30. 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.

31. EKV et progressiva

32. 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)

33. 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

34. 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.

35. GJB6 (Cx30)Clouston syndrome (Hidroticectodermal dysplasia • Hypotrichosis. • Nail dystrophy. • Palmoplanter hyperkeratosis. • Teeth, sweat and sebaceous glands are not affected.

36. 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

37. 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.