RESUMO
The multiplicity of functions served by intercellular gap junctions is reflected by the variety of phenotypes caused by mutations in the connexins of which they are composed. Mutations in the connexin26 (Cx26) gene ( GJB2 ) at 13q11-q13 are a major cause of autosomal recessive hearing loss (DFNB1), but have also been reported in autosomal dominant deafness (DFNA3). We now report a Cx26 mutation in three families with mutilating keratoderma and deafness [Vohwinkel's syndrome (VS; MIM 124500), as originally described]. VS is characterized by papular and honeycomb keratoderma associated with constrictions of digits leading to autoamputation, distinctive starfish-like acral keratoses and moderate degrees of deafness. In a large British pedigree, we have mapped the defect to the Cx26 locus. All 10 affected members were heterozygous for a non-conservative mutation, D66H, in Cx26. The same mutation was found subsequently in affected individuals from two unrelated Spanish and Italian pedigrees segregating VS, suggesting that D66H in Cx26 is a common mutation in classical VS. This mutation occurs at a highly conserved residue in the first extracellular domain of the Cx26 molecule, and may exert its effects by interfering with assembly into connexons, docking with adjacent cells or gating properties of the gap junction. Our results provide evidence that a specific mutation in Cx26 can impair epidermal differentiation, as well as inner ear function.
Assuntos
Conexinas/genética , Surdez/genética , Ceratodermia Palmar e Plantar/genética , Mutação de Sentido Incorreto , Adolescente , Adulto , Idoso , Sequência de Aminoácidos , Criança , Cromossomos Humanos Par 13 , Conexina 26 , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Linhagem , Homologia de Sequência de Aminoácidos , SíndromeAssuntos
Balanite (Inflamação)/etiologia , Fimose/cirurgia , Adulto , Humanos , Masculino , Complicações Pós-OperatóriasAssuntos
Bleomicina/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Melanoma/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Avaliação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Four cases of keratoma hereditaria mutilans (Vohwinkel syndrome) are reported in two families, whereas clinic, metabolic, radiologic, histologic and cytogenetic aspects, the association with other processes, and therapeutic possibilities.