Mutations in GJA1 (connexin 43) are associated with non-syndromic autosomal recessive deafness

Abstract

Mutations in four members of the connexin gene family have been shown to underlie distinct genetic forms of deafness, including GJB2 [connexin 26 (Cx26)], GJB3 (Cx31), GJB6 (Cx30) and GJB1 (Cx32). We have found that alterations in a fifth member of this family, GJA1 (Cx43), appear to cause a common form of deafness in African Americans. We identified two different GJA1 mutations in four of 26 African American probands. Three were homozygous for a Leu-->Phe substitution in the absolutely conserved codon 11, whereas the other was homozygous for a Val-->Ala transversion at the highly conserved codon 24. Neither mutation was detected in DNA from 100 control subjects without deafness. Cx43 is expressed in the cochlea, as is demonstrated by PCR amplification from human fetal cochlear cDNA and by RT-PCR of mouse cochlear tissues. Immunohistochemical staining of mouse cochlear preparations showed immunostaining for Cx43 in non-sensory epithelial cells and in fibrocytes of the spiral ligament and the spiral limbus. To our knowledge this is the first alpha connexin gene to be associated with non-syndromic deafness. Cx43 must also play a critical role in the physiology of hearing, presumably by participating in the recycling of potassium to the cochlear endolymph.

Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

“…The most frequent causative gene for nonsyndromatic SNHL is GJB2 ( CX26 ) (Smith et al, 2014 2014). Although less frequent, mutations in GJB6 ( CX30 ) (Grifa et al, 1999; del Castillo et al, 2002) and GJA1 (CX43) (Liu et al, 2001; Hong et al, 2010) have also been linked to SNHL. These gap junction proteins are thought to play a role in maintaining cochlear ion homeostasis and the endocochlear potential, as shown in Gjb6 ‐deficient mice (Teubner et al, 2003), by passively recycling K + ions back to the stria vascularis.…”

No evidence for clinical utility in investigating the connexin genes GJB2, GJB6 and GJA1 in non-syndromic hearing loss in black Africans

“…The GJB6-D13S1830 deletion is present in up to 9.7% of people of European descent, [11] and represents the second leading genetic cause of nonsyndromic deafness. When GJA1 mutations were detected in African Americans, [12] GJA1 emerged as a possible candidate for hearing loss in indigenous Africans. However, failure by investigators to differentiate between GJA1 and its pseudogene led to this hypothesis being discarded.…”

Effectiveness of sequencing connexin 26 (GJB2) in cases of familial or sporadic childhood deafness referred for molecular diagnostic testing

“…Its occurrence as a frequent mutation or founder mutation remains to be studied in different populations. In addition, the noncoding exon 1 of Cx26 24 and the Cx43 (GJA1) 56 are also reasonable candidates for searching for a second mutation.…”