Report on a Novel Mutation, p.Leu213X, in Connexin‐26 Protein

Abstract

Objectives: Nonsyndromic sensorineural hearing loss (HL) is predominantly inherited in an autosomal recessive pattern. The DFNB1 locus, at chromosome 13q11-q12, includes the GJB2 and GJB6 genes, which encode connexin-26 (Cx26) and connexin-30 (Cx30), respectively. The objective of this study was to assess the genetic etiology of HL in a Portuguese family, presenting two siblings with nonsyndromic sensorineural moderate and severe HL, respectively. Methods: The individuals from one Portuguese family were evaluated by pure tone audiometry and blood samples were collected for DNA extraction. Polymerase chain reaction (PCR) amplification of GJB2 coding region followed standard methodologies. PCR products were automatically sequenced in both directions. A random control sample of 480 Portuguese individuals was also screened for the GJB2 coding region. Results: A novel mutation, c.638T>A (p.Leu213X), was identified in the GJB2 gene. This nonsense mutation was found in both siblings, and was inherited from their hearing father. Molecular analysis showed that the two siblings were also heterozygous for c.333-334delAA, a previously described GJB2 deletion, inherited from their hearing mother. The novel mutation wasn’t found in the control sample. The mutation p.Leu213X is located to the C-terminus domain of the connexin-26 and changes the codon 213, that codes for a highly conserved and slowly evolving residue of this protein, to a STOP codon, leading to the deletion of the last 14 amino acids of the protein. Conclusions: The HL of the two Portuguese siblings is most probably due to the presence of the c.333-334delAA deletion and the p.Leu213X novel mutation, in compound heterozygosity.