Connexin30 mutations responsible for hidrotic ectodermal dysplasia cause abnormal hemichannel activity

Clouston syndrome or hidrotic ectodermal dysplasia (HED) is a rare dominant genodermatosis characterized by palmoplantar hyperkeratosis, generalized alopecia and nail defects. The disease is caused by mutations in the human GJB6 gene which encodes the gap junction protein connexin30 (Cx30). To gain insight into the molecular mechanisms underlying HED, we have analyzed the consequences of two of these mutations (G11R Cx30 and A88V Cx30) on the functional properties of the connexons they form. Here, we show that the distribution of Cx30 is similar in affected palmoplantar skin and in normal epidermis. We further demonstrate that the presence of the wild-type protein (wt Cx30) improves the trafficking of mutated Cx30 to the plasma membrane where both G11R and A88V Cx30 co-localize with wt Cx30 and form functional intercellular channels. The electrophysiological properties of channels made of G11R and A88V Cx30 differ slightly from those of wt Cx30 but allow for dye transfer between transfected HeLa cells. Finally, we document a gain of function of G11R and A88V Cx30, which form functional hemichannels at the cell surface and, when expressed in HeLa cells, generate a leakage of ATP into the extracellular medium. Such increased ATP levels might act as a paracrine messenger that, by altering the epidermal factors which control the proliferation and differentiation of keratinocytes, may play an important role in the pathophysiological processes leading to the HED phenotyp

Analyse fonctionnelle des mutations du gène GJB6 codant la connexine30 humaine responsable du syndrome de Clouston

La dysplasie ectodermique hidrotique ou syndrome de Clouston est une génodermatose rare qui se caractérise par une hyperkératose palmoplantaire, une alopécie généralisée et une dystrophie des ongles. Nous avons démontré que ce syndrome est dû à des mutations dans le gène GJB6, qui code la connexine30 humaine, pour lequel nous avons déterminé la structure génomique et analysé la région promotrice. L'analyse fonctionnelle des formes mutées de la protéine a permis de démontrer que leur transport bénéficie de la présence de la Cx30 sauvage et que les jonctions communicantes formées de Cx30 mutées sont fonctionnelles. Cependant, les Cx30 mutées se sont avérées capables de former des hemicanaux non-appariés constitutivement ouverts à la surface de la cellule qui entraînent une fuite d'ATP vers le milieu extracellulaire. Cette observation nous a permis d'émettre l'hypothèse que cette libération d'ATP est à l'origine du phénotype observé au niveau de l'épiderme atteint.EVRY-BU (912282101) / SudocSudocFranceF

Mutations in GJB6 cause hidrotic ectodermal dysplasia

International audienceLandouzy-Dejerine muscular dystrophy is a rare hereditary disease with prevalence of 0.9 to 1.4 in 100,000. Clinically the disease is characterized by weakness and atrophy of the facial and shoulder girdle muscles. It is caused by partial deletion of the 3.3-kb subtelomeric D4Z4 repeat on chromosome 4 (locus 4q35). This paper presents a critical review of the literature data and hypotheses explaining molecular mechanisms of progressive fascioscapulohumeral muscular dystrophy