RESUMO
Mutations in connexin26, a cutaneous gap junction protein, cause a wide variety of skin disorders including keratitis-ichthyosis-deafness syndrome (KID). We previously delineated a phenotype distinct from KID, hypotrichosis-deafness syndrome, caused by the mutation p.Asn14Lys in connexin26. However, a different mutation at the same location, p.Asn14Tyr, was reported to cause a disorder similar to KID. Distinct substitutions cause different conformational changes to the protein, each with unique consequences for its behaviour. This may explain the phenotypic differences. We found the previously described mutation p.Asn14Tyr in connexin26 in two patients from Brazil and Poland, and observe quite distinct phenotypes distinguishable from classical KID syndrome. We assessed functional consequences of p.Asn14Tyr and p.Asn14Lys, using fluorescently labelled proteins and parachute assay, comparing them with the classical KID mutation p.Asp50Asn. Our analyses show that p.Asn14Tyr, p.Asn14Lys and p.Asp50Asn have different consequences for protein localization and gap junction permeability. However, the differences between the phenotypes we observed cannot be readily explained from effects on protein trafficking or gap junction permeability.
