Abstract: Homozygous alterations in the gap junction protein GJB2 (connexin 26), within the DFNB1 locus, are responsible for up to 50% of autosomal recessive non-syndromic hearing impairment (NSHI). Analysis of the GJB2 promoter revealed the potential importance of T-228C in the regulation of GJB2 expression. Of regulatory factors known to be expressed in the inner ear, the T-228C transition would delete potential binding sites for the X-box binding protein (RFX1) and the H6 homeobox 3 (HMX3/Nk×5.1) transcription factor which has been linked to hearing impairment. These results suggest that T-228C may represent the most common mutation associated with development of NSHI in Caucasian populations identified to date and should be included in worldwide newborn screening programs for NSHI.

Abstract: Homozygous alterations in the gap junction protein GJB2 (connexin 26), within the DFNB1 locus, are responsible for up to 50% of autosomal recessive non-syndromic hearing impairment (NSHI). Mutations have been described throughout the coding region and more rarely, within the splice donor site. To further investigate the role of GJB2 in NSHI, we have now screened the putative 5? regulatory region for novel alterations. In idiopathic cases of NSHI lacking known pathogenic alterations in GJB2, we have now identified a T?C transition 228 bp proximal to the transcriptional start site (T-228C) present at a homozygous frequency of 0.2, which is significantly overrepresented in comparison to the predicted homozygous allele frequencies in the healthy population (0.0144). In a NSHI family, inheritance of T-228C was shown to segregate on independent chromosomes with HI in conjunction with heterozygous inheritance of 35 delG, the most common Caucasian mutation in the GJB2 coding region.