A deletion mutation in GJB6 cooperating with a GJB2 mutation in trans in non-syndromic deafness: A novel founder mutation in Ashkenazi Jews

Abstract

A deletion of at least 140 kb starting approximately 35kb upstream (telomeric) to the GJB2 (CX26) gene was identified in 7 patients from 4 unrelated Jewish Ashkenazi families with non-syndromic hearing loss. These patients were heterozygous for one of the common mutations 167delT or 35delG in the GJB2 gene in trans to the deletion. The deletion started at 5' side of the GJB6 (CX30) gene including the first exon and it did not affect the integrity of the GJB2 gene. The deletion mutation segregated together with the hearing loss, and was not found in a control group of 100 Ashkenazi individuals. We suggest that the deletion is a recessive mutation causing hearing loss in individuals that are double heterozygous for the deletion and for a mutation in the GJB2 gene. The effect of the deletion mutation could be due to a digenic mode of inheritance of GJB2 and GJB6 genes that encode two different connexins; connexin 26 and connexin 30, or it may abolish control elements that are important in the expression of the GJB2 gene in the cochlea. Regardless which of the options is valid, it is apparent that the deletion mutation provides a new insight into connexin function in the auditory system. The deletion mutation was on the same haplotypic background in all the families, and therefore is a founder mutation that increases the impact of GJB2 in the etiology of prelingual recessive non-syndromic hearing loss in the Ashkenazi population.

The 342-kb deletion inGJB6is not present in patients with non-syndromic hearing loss from Austria

“…The deletion was also detected in trans in 4 of 6 HL patients heterozygous for GJB2 mutations and in the homozygous state in one case of congenital profound deafness in France (Pallares-Ruiz et al, 2002). Moreover, in seven NSHL patients being heterozygous for GJB6 mutations from four unrelated Jewish Ashkenazi families the GJB6 deletion was found (Lerer et al, 2001). Digenic inheritance in those cases is supported by the findings that both genes, GJB2 and GJB6, encode for gap junction proteins, connexin 26 and connexin 30, respectively, and are expressed in the same cells in the rat cochlea and in the cochlea of the 22-week-old human embryo (Lautermann et al, 1999).…”

Connexin-Mediated Signaling in Nonsensory Cells Is Crucial for the Development of Sensory Inner Hair Cells in the Mouse Cochlea

“…This cell syncytium does not include the sensory IHCs or OHCs (e.g., Oesterle and Dallos, 1990;Jagger and Forge, 2006;Majumder et al, 2010), yet connexins have been shown to be crucial for hearing as deletion of Cx26 (e.g., Cohen-Salmon et al, 2002;Crispino et al, 2011) and mutation of Cx26 or Cx30 cause hearing loss in mice (Schü tz et al, 2010) and humans (Wang et al, 2011e.g., del Castillo and del Castillo, 2012). Deletion of Cx30 is normally associated with substantial downregulation of Cx26 expression in Cx30(Ϫ/Ϫ) mice as well as in DFNB1 patients (Lerer et al, 2001;Pallares-Ruiz et al, 2002;del Castillo et al, 2002;Rodriguez-Paris and Schrijver, 2009) mouse, which were elicited by applying hyperpolarizing and depolarizing current injections. Recordings were performed at room temperature.…”

Genetic causes of nonsyndromic hearing loss in Iran in comparison with other populations

“…A few point mutations in the GJB6 gene have been found to associate with autosomal dominant HL and hidrotic ectodermal dysplasia. 35 Four GJB6 large deletions, a 140 kb deletion 36 or a 150 kb deletion, 37 named del(GJB6-D13S1830) 342 kb, 38 del(GJB6-D13S1854) 232 kb, 39 a 920 kb deletion 40 and del(chr13:19,837,344-19,968,698), 41 have been described to bring about HL in association with a single mutation in the GJB2 gene. Existence of several breakpoints within this region suggests that other unknown deletions may be responsible for GJB2 heterozygotes.…”