Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment

Abstract

Mutations in the connexin 31 (GJB3) gene have been found in subjects with dominant and recessive deafness and in patients with erythrokeratodermia variabilis. We report here a dominant mutation in the GJB3 gene (D66del) in a family affected with peripheral neuropathy and sensorineural hearing impairment. A wide range of disease severity for peripheral neuropathy, from asymptomatic cases to subjects with chronic skin ulcers in their feet and osteomyelitis leading to amputations, was detected in D66del patients. Mild, often asymmetrical, hearing impairment was found in all but one patient with mutation D66del of this family and the same mutation was present in an independent family ascertained because of hearing impairment. We have found mouse connexin 31 (Gjb3) gene expression in the cochlea and in the auditory and sciatic nerves, showing a pattern similar to that of Gjb1 (connexin 32), of which the human ortholog (GJB1) is involved in X-linked peripheral neuropathy. This expression pattern, together with auditory-evoked brainstem anomalous response in D66del patients, indicates that hearing impairment due to GJB3 mutations involves alterations in both the cochlea and the auditory nerve. Peripheral neuropathy is the third phenotypic alteration linked to GJB3 mutations, which enlarges the list of genes that cause this group of heterogeneous disorders.

Update of the Spectrum ofGJB2Mutations in 107 Patients with Nonsyndromic Hearing Loss in the Fujian Population of China

“…However, when the whole GJB6 coding region was screened for deletions, such as del (GJB6-D13S1830), in 655 hearing impaired patients in Central China, the del (GJB6-D13S1830) or other mutations in the GJB6 gene were not observed, suggesting that mutation of GJB6 is not a common cause of NSHL among the Chinese population (Chen et al, 2012). Therefore, other connexin genes, such as GJB3 and GJA1 or other genes causing NSHL, which have not yet been analyzed, may contribute to the mutation spectrum in the eight probands with only the heterozygous c.235delC mutation in the Fujian population (López-Bigas et al, 2001;Thönnissen et al, 2002;Ramzan et al, 2013).…”

Clinical evidence of the nonpathogenic nature of the M34T variant in the connexin 26 gene

“…However, the R32W variant of GJB3 has been demonstrated not to be the cause of deafness or skin disease in Spanish patients, even in association with GJB2 mutations. 22 In his report, Kelsell et al did not consider that the difference of the severity of the hearing defect could be age dependent as in an other family also carrying D66H 21 in which the adults members suffered from moderate to severe hearing loss and the children were only mildly affected. The pedigree of Kelsell's family is consistent with this hypothesis because the younger patient (III3) has PPK without deafness.…”

Cx31 is assembled and trafficked to cell surface by ER-Golgi pathway and degraded by proteasomal or lysosomal pathways

“…Mutations in Cx31 would cause erythrokeratodermia variabilis (EKV), hearing impairment, and peripheral neuropathy, respectively [4][5][6][7]. However, the mechanism of Cx31 in the pathogenesis of these diseases remains unclear.…”