Analysis of the presence of the GJB6 mutations in patients heterozygous for GJB2 mutation in Brazil

Abstract

Mutations in the GJB2 gene, mainly 35delG, are responsible for most autosomal recessive inherited genetic hearing loss. The audiometric standard of these hearing losses remains inconsistent and other genes, such as GJB6, have been involved in association with GJB2. The objective of the study was to identify the deletions del(GJB6-D13S1830) and del(GJB6-D13S1854) in patients heterozygous for 35delG/GJB2 and analyze the phenotype they present. 101 patients with mild to profound degree of sensorineural hypoacusis were evaluated. The allele-specific PCR technique was used to identify 35delG. The del(GJB6-D13S1830) and del(GJB6-D13S1854) were identified through the PCR multiplex technique. 90% of the subjects presented a normal genotype for the analyzed mutations; 6.93% were shown to be heterozygous for 35delG/GJB2 and 1% presented compound heterozygosis GJB2/GJB6). The data found reinforced the hypothesis of an interaction of more than one gene as the cause of autosomal recessive genetic hearing loss and emphasized the importance of an early diagnosis for appropriate intervention.

Audiological Phenotypes of Connexin Gene Mutation Patterns: A Glance at Different GJB2/GJB6 Gene Mutation Profiles

“…In our population, the five patients who had GJB2 mutations with simple heterozygosis showed the mildest degree of hearing impairment, with an average PTA of 50.38 ± 27.59 dB. This is consistent with the fact that, although the inheritance of most Connexin gene mutations has classically been considered to be autosomal-recessive, accumulating evidence has reported GJB2 mutations in heterozygosis to be a possible cause of congenital sensorineural hypoacusis [34]. In particular, patients presenting with GJB2 gene mutations in a heterozygosis pattern appear to show a milder phenotype in terms of hearing loss, seemingly due to the presence of a certain amount of wild-type Connexin 26 gene product, which may keep cochlear structures in a state of partially functioning [35,36].…”

“…In a recent review, Mao et al [11] reported a complete and updated classification of the currently known associations between every missense GJB2 variant, the molecular mechanisms underlying hemichannel and gap junction functions, interactions with other co-expressed connexins like GJB6, and the clinical phenotypes. However, apart from highly prevalent mutations patterns, such as GJB2 (35delG/35delG), it might be difficult to obtain genetically homogeneous groups suitable to compare clinical data [23,34].…”

Unraveling of Enigmatic Hearing-Impaired GJB2 Single Heterozygotes by Massive Parallel Sequencing

“…Large deletions in GJB6 (del [GJB6-D13S1830] and del [GJB6-D13S1854]) are frequently detected in a trans configuration with a monoallelic GJB2 mutation in certain populations. 33,35,39 Based on these findings, it was previously hypothesized that variations in GJB2 and GJB6 in trans can cause SNHL through digenic inheritance. 33,40 However, subsequent studies revealed that GJB6 deletions result in an allele-specific lack of GJB2 mRNA expression, contributing to SNHL in a manner not resulting from digenic inheritance.…”

Novel mutations inGJB6andGJB2in Clouston syndrome

“…The relationship between GJB2 and GJB6 is complicated. According to previous reports, both mutations in GJB6 and GJB2 are responsible for keratosis–ichthyosis–deafness (KID) syndrome and AD hearing loss . A high level of homology between GJB2 and GJB6 probably induces the combination gene mutation in CS .…”