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A Novel Autosomal Recessive Gjb2-Associated Disorder: Ichthyosis Follicularis, Bilateral Severe Sensorineural Hearing Loss, and Punctate Palmoplantar Keratoderma Publisher Pubmed



Youssefian L1, 2, 3 ; Vahidnezhad H1, 4 ; Saeidian AH1, 3 ; Mahmoudi H5 ; Karamzadeh R6 ; Kariminejad A7 ; Huang J1 ; Li L8 ; Jannace TF8 ; Fortina P9, 10 ; Zeinali S4 ; White TW8 ; Uitto J1
Authors

Source: Human Mutation Published:2019


Abstract

Ichthyosis follicularis, a distinct cutaneous entity reported in combination with atrichia, and photophobia has been associated with mutations in MBTPS2. We sought the genetic cause of a novel syndrome of ichthyosis follicularis, bilateral severe sensorineural hearing loss and punctate palmoplantar keratoderma in two families. We performed whole exome sequencing on three patients from two families. The pathogenicity and consequences of mutations were studied in the Xenopus oocyte expression system and by molecular modeling analysis. Compound heterozygous mutations in the GJB2 gene were discovered: a pathogenic c.526A>G; p.Asn176Asp, and a common frameshift mutation, c.35delG; p.Gly12Valfs*2. The p.Asn176Asp missense mutation was demonstrated to significantly reduce the cell–cell gap junction channel activity and increase the nonjunctional hemichannel activity in the Xenopus oocyte expression system. Molecular modeling analyses of the mutant Cx26 protein revealed significant changes in the structural characteristics and electrostatic potential of the Cx26, either in hemichannel or gap junction conformation. Thus, association of a new syndrome of an autosomal recessive disorder of ichthyosis follicularis, bilateral severe sensorineural hearing loss and punctate palmoplantar keratoderma with mutations in GJB2, expands the phenotypic spectrum of the GJB2-associated disorders. The findings attest to the complexity of the clinical consequences of different mutations in GJB2. © 2018 Wiley Periodicals, Inc.
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