Mutation of a transcription factor, TFCP2L3, causes progressive autosomal dominant hearing loss, DFNA28

Abstract

We ascertained a large American family with an autosomal dominant form of progressive non-syndromic sensorineural bearing loss. After excluding linkage to known deafness loci, we performed a genome-wide scan and found linkage to marker GAAT1A4 on chromosome 8q22 (LOD = 5.12 at θ = 0), and this locus was designated DFNA28. Sequencing of six candidate genes in the 1.4cM linked region identified a frameshift mutation (1609-1610insC) resulting in a premature translation stop codon in exon 14 of the gene TFCP2L3 (transcription factor cellular promoter 2-like 3). TFCP2L3 is a member of a family of transcription factor genes whose archetype is TFCP2, a mammalian homolog of the Drosophila gene grainyhead. Northern blot analyses and in situ hybridization studies show that mouse Tfcp213 is expressed in many epithelial tissues, including cells lining the cochlear duct, at embryonic day 18.5 and postnatal day 5.