Allele-specific impairment of GJB2 expression by GJB6 deletion del(GJB6-D13S1854)

• Published in: PloS one Vol. 6; no. 6; p. e21665
• Main Authors: Rodriguez-Paris, Juan, Tamayo, Marta L, Gelvez, Nancy, Schrijver, Iris
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 29.06.2011; Public Library of Science (PLoS)
• Subjects: Alleles; Biology; Connexin 26; Connexin 30; Connexins - genetics; Gene deletion; Gene expression; Genes; Genetic aspects; GJB2 protein; Hearing loss; Hearing Loss, Sensorineural - genetics; Heredity; Humans; Hypotheses; Medicine; Mutation; Polymorphism, Restriction Fragment Length - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA; Sequence Deletion - genetics; Studies; Transcription; Colombia; United States > US; California
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0021665

Mutations in the GJB2 gene, which encodes connexin 26, are a frequent cause of congenital non-syndromic sensorineural hearing loss. Two large deletions, del(GJB6-D13S1830) and del(GJB6-D13S1854), which truncate GJB6 (connexin 30), cause hearing loss in individuals homozygous, or compound heterozygous for these deletions or one such deletion and a mutation in GJB2. Recently, we have demonstrated that the del(GJB6-D13S1830) deletion contributes to hearing loss due to an allele-specific lack of GJB2 mRNA expression and not as a result of digenic inheritance, as was postulated earlier. In the current study we investigated the smaller del(GJB6-D13S1854) deletion, which disrupts the expression of GJB2 at the transcriptional level in a manner similar to the more common del(GJB6-D13S1830) deletion. Interestingly, in the presence of this deletion, GJB2 expression remains minimally but reproducibly present. The relative allele-specific expression of GJB2 was assessed by reverse-transcriptase PCR and restriction digestions in three probands who were compound heterozygous for a GJB2 mutation and del(GJB6-D13S1854). Each individual carried a different sequence variant in GJB2. All three individuals expressed the mutated GJB2 allele in trans with del(GJB6-D13S1854), but expression of the GJB2 allele in cis with the deletion was almost absent. Our study clearly corroborates the hypothesis that the del(GJB6-D13S1854), similar to the larger and more common del(GJB6-D13S1830), removes (a) putative cis-regulatory element(s) upstream of GJB6 and narrows down the region of location.