title: Molecular analysis of connexin26 asparagine14 mutations associated with syndromic skin phenotypes.
abstract: 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.
authors.affiliation: Department of Dermatology, Maastricht University Medical Center, Maastricht, the Netherlands. eadezwartstorm@gmail.com
authors.forename: Eugene A
authors.initials: EA
authors.lastname: de Zwart-Storm
authors.forename: Rafael F M
authors.initials: RF
authors.lastname: Rosa
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Martin
authors.forename: Regina
authors.initials: R
authors.lastname: Foelster-Holst
authors.forename: Jorge
authors.initials: J
authors.lastname: Frank
authors.forename: Ana E K
authors.initials: AE
authors.lastname: Bau
authors.forename: Paulo R G
authors.initials: PR
authors.lastname: Zen
authors.forename: Carla
authors.initials: C
authors.lastname: Graziadio
authors.forename: Giorgio A
authors.initials: GA
authors.lastname: Paskulin
authors.forename: Miriam A
authors.initials: MA
authors.lastname: Kamps
authors.forename: Michel
authors.initials: M
authors.lastname: van Geel
authors.forename: Maurice A M
authors.initials: MA
authors.lastname: van Steensel
mesh_terms: D000328:Adult; D001216:Asparagine / Q000235:genetics*; D001224:Aspartic Acid / Q000235:genetics; D002462:Cell Membrane / Q000378:metabolism; D002648:Child; D000072259:Connexin 26; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D005452:Fluoresceins / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism; D006367:HeLa Cells; D034381:Hearing Loss / Q000235:genetics; D006801:Humans; D006983:Hypertrichosis / Q000235:genetics / Q000473:pathology; D007645:Keratoderma, Palmoplantar / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D007642:Keratosis / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D008239:Lysine / Q000235:genetics; D008297:Male; D020125:Mutation, Missense / Q000502:physiology*; D009264:Nails, Malformed / Q000235:genetics / Q000473:pathology; D021381:Protein Transport / Q000235:genetics; D012867:Skin / Q000473:pathology; D012871:Skin Diseases / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D013577:Syndrome; D014162:Transfection; D014443:Tyrosine / Q000235:genetics
chemical_list: D017630:Connexins; D005452:Fluoresceins; C000607042:GJB2 protein, human; D000072259:Connexin 26; D001224:Aspartic Acid; D014443:Tyrosine; D001216:Asparagine; D008239:Lysine; C007740:fluorexon