Further mutations in Brain 4 (POU3F4) clarify the phenotype in the X-linked deafness, DFN3

Otic mesenchyme expression of Cre recombinase directed by the inner ear enhancer of the Brn4/Pou3f4 gene

“…A region of evolutionarily conservation was detected within a region of the human genome that is deleted in several patients with mutations in the POU3F4 gene, consistent with the hypothesis that this region is necessary for the expression of the Brn4 gene in the otic mesenchyme (Bitner-Glindzicz et al, 1995;Phippard et al, 2000). This enhancer region has been demonstrated to drive the expression of Cre recombinase in the otic mesenchyme.…”

“…In this radiation-induced allele of the gene, an inversion of the central portion of the X chromosome results in a chromosomal breakpoint that lies a considerable distance upstream of the ORF, consistent with the hypothesis that an enhancer that directs expression to the otic mesenchyme lies far upstream of the ORF (Phippard et al, 2000). Mutational analyses of the human ortholog, POU3F4, demonstrated that small deletions mapping 920 kb upstream of the ORF result in a congenital hearing loss phenotype that is indistinguishable from deletions encompassing the ORF (Bitner-Glindzicz et al, 1995). Bitner-Glindzicz and her colleagues hypothesized that these upstream deletions eliminated an otic enhancer region.…”

“…The figure depicts the analysis of the ECR browser program (http://ecrbrowser.dcode.org/) of the SalI-PstI fragment of the human X chromosome that lies 920 kb upstream of the human POU3F4 gene (hg18 chrX:81726886-81729742). This ECR lies in a minimal deletion of an upstream region that results in congenital deafness whose phenotype is consistent with a null allele of the POU3F4 gene (Bitner-Glindzicz et al, 1995). The base genome in this plot is the human sequence, and pairwise comparison with the genomes of mouse, dog, opossum, and xenopus are shown.…”

A duplication/paracentric inversion associated with familial X-linked deafness (DFN3) suggests the presence of a regulatory element more than 400 kb upstream of the POU3F4 gene

“…We cloned and characterized the human homolog of Brain 4, POU3F4, and were able to position the gene in the critical region for DFN3. In seven unrelated patients with DFN3 but not in 100 control X-chromosomes, small mutations were found in the POU3F4 gene that result in truncation of the predicted protein or in non-conservative amino acid substitutions - (14,15). Surprisingly, the intronless POU3F4 gene was found to be located up to 400 kb distal to four minideletions associated with typical DFN3 (11,14).…”

Autosomal and X-Linked Auditory Disorders

“…POU3F4 mutations were detected in some patients with DFN3-linked hearing loss, as well as in families with X-linked hearing loss that were too small to map the phenotype (Bitner-Glindzicz et al 1995 Kok et al 1996). The genomic DNA of one DFN3 patient shows a complex chromosomal rearrangement involving a paracentromeric inversion 320 kb from POU3F4 and a 150 to 170 kb duplication proximal to POU3F4, but the coding region of POU3F4 is intact.…”