Prospective variants screening of connexin genes in children with hearing impairment: genotype/phenotype correlation

Abstract

The crucial role of gap junctions, which are composed of connexin (CX) protein, in auditory functions has been confirmed by numerous studies. In this study, we investigate the prevalence and phenotype/genotype correlation of connexin (CX) gene family variants in a cohort of children with nonsyndromic hearing loss (HL). A total of 253 unrelated children with nonsyndromic HL were screened for the presence of variants in 6 genes of the CX gene family. The prevalence of CX gene variants in 253 patients was 19.7% (50/253). We found the frequency of a sloping audiometric configuration was significantly higher for children with GJB2 and GJB3 variants than for those with GJB4 and GJC3 variants (Adjusted OR = 4.89, p < 0.001). Conversely, the frequency of a flat audiometric configuration was significantly higher for children with GJB4 and GJC3 variants than for those with GJB2 and GJB3 variants (adjusted OR = 7.76, p < 0.001). The relative frequencies of multiplex families was significantly higher for children with GJB3 variants than for those with GJB2, GJB4, and GJC3 variants (Adjusted OR = 11.33, p = 0.003). Our results suggest the variants of GJC3, GJB4, and GJB3 may be the common genetic risk factor, after variants of GJB2, for the development of nonsyndromic HL in Taiwan. These data can be effectively applied to direct the clinical evaluation of children with CX gene variants.

Human Connexin30.2/31.3 (GJC3) does not Form Functional Gap Junction Channels but Causes Enhanced ATP Release in HeLa Cells

“…A previous investigation showed that mouse Cx29 did not induce intercellular conductances when expressed alone in mouse neuroblastoma cells [12]. Our earlier study established that mutations of GJC3 are associated with nonsyndromic hearing loss [17,18]. Moreover, our data demonstrate that the p.E269D missense mutation of CX30.2/CX31.3 results in the accumulation of the CX30.2/CX31.3 mutant protein in the endoplasmic reticulum, rather than in the cytoplasmic membrane [19].…”

Association between mutations in the gap junction β4 gene and nonsyndromic hearing loss: Genotype-phenotype correlation patterns

“…Few studies have been conducted on the correlation of variants in the GJB4 gene and its phenotype in patients with nonsyndromic hearing loss. These previous studies were compared and summarized in Table I (13,19,20). In these results, the proportion of patients with GJB4 variants was determined to be 4.09% (21/513).…”

“…In the study, five amino acid variants (c.307 C>T, c.371 G>A, c.478 C>T, c.507 C>G and c.611 A>C) were detected in deaf individuals without skin disorders (19). In our previous genetic survey of 373 individuals, including 253 with nonsyndromic deafness and 120 with normal hearing, 11 mutations were detected in the patients with hearing loss (20). However, the correlation between the GJB4 gene mutations and the audiology phenotype in deaf patients was not examined.…”

Government-funded universal newborn hearing screening and genetic analyses of deafness predisposing genes in Taiwan

“…In the majority of studies which researched the mutations associated with prelingual hearing impairment in the Taiwanese population, the hearing-impaired subjects were mainly recruited from students of the rehabilitation schools for the deaf [12][13][14][15]. Some of the studies purely focused on the GJB2 gene [12,13], or targeted only a few deafness-associated mutations [16].…”