title: Allele-specific impairment of GJB2 expression by GJB6 deletion del(GJB6-D13S1854).
abstract: 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.
authors: Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
authors: Juan
authors: J
authors: Rodriguez-Paris
authors: Marta L
authors: ML
authors: Tamayo
authors: Nancy
authors: N
authors: Gelvez
authors: Iris
authors: I
authors: Schrijver
mesh_terms: D000483:Alleles; D000072259:Connexin 26; D000075302:Connexin 30; D017630:Connexins / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics; D006801:Humans; D012150:Polymorphism, Restriction Fragment Length / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion / Q000235:genetics
chemical_list: D000075302:Connexin 30; D017630:Connexins; C000607042:GJB2 protein, human; C491020:GJB6 protein, human; D000072259:Connexin 26