Nolan, L.S.; (2006) Susceptibility to late onset hearing loss: an investigation into genetic variation at the Brn-3c locus. Doctoral thesis , University of London.

PDF U592183.pdf Download (29MB)

Abstract

BrnSc (BrnS.l, POU4F3) encoding a POU domain transcription factor is a candidate gene for late onset sensorineural hearing loss, which is exhibited by a large proportion of the ageing population. To identify common sequence variants at the Brn-3c locus mutation scanning of the BrnSc cDNA, intron and 5'-flanking region was performed by PCR-SSCP analysis in 45 members of the general population. Seven polymorphic sites were identified of which five within the Bm-Sc 5'-flanking region appear common. A functional screening approach utilising in-vitro assays suggests that at least three common sequence variants in the Brn-Sc 5'-flanking region could have a functional affect: -566(GT)i7-23, -1391A>C and a complex multi-allelic poly-G polymorphism at - 3432 that exhibits multiple variations in length together with single base substitutions within the guanine repeat. The -3432poly-G polymorphism modifies the binding affinity of an OC-2 derived nuclear protein and there is convincing evidence that this is the transcription factor SP1. Use of purified human recombinant SP1 protein, in-vitro translated SP1 and in-vitro translated SP3 confirms that the -3432polyG polymorphism modulates a high affinity SP family binding site and evidence suggests that this alters the regulation of the BrnSc promoter when SP1 levels are limiting, p<0.05. Moreover, the data suggest a functional interaction between the -3432poly-G polymorphism and the -566(GT)i7.23 repeat which associate to determine the response of the Brn-3c gene to SP1. Similarly, evidence suggests that the variant allele, -1391C has a reduced affinity for an OC-2 derived nuclear protein and this is consistent with a significant decrease in basal activity of the Brn-Sc promoter, pC were genotyped for a pilot association study but allelic frequencies were not found to significantly differ between the patient and control populations examined (by %2 analysis). Further large-scale population studies are required to establish whether these common sequence variants are associated with late onset hearing loss.

Download activity - last month

Export as CSVJSONXML

Download activity - last 12 months

Export as XMLCSVJSON

Downloads by country - last 12 months

Export as JSONCSVXML

Archive Staff Only

View Item