Abstract
Autosomal dominant hearing loss is highly heterogeneous. Hearing impairment mainly involves the mid-frequencies (500–2000 Hz) in only a low percentage of the cases. In a Dutch family with autosomal dominant mid-frequency/flat hearing loss, genome-wide SNP analysis combined with fine mapping using microsatellite markers mapped the defect to the DFNA8/12 locus, with a maximum two-point LOD score of 3.52. All exons and intron–exon boundaries of the TECTA gene, of which mutations are causative for DFNA8/12, were sequenced. Only one heterozygous synonymous change in exon 16 (c.5331G>A; p.L1777L) was found to segregate with the hearing loss. This change was predicted to cause the loss of an exonic splice enhancer (ESE). RT-PCR using primers flanking exon 16 revealed, besides the expected PCR product from the wild-type allele, a smaller fragment only in the affected individual, representing part of an aberrant TECTA transcript lacking exon 16. The aberrant splicing is predicted to result in a deletion of 37 amino acids (p.S1758Y/G1759_N1795del) in α-tectorin. Subsequently, the same mutation was detected in two out of 36 individuals with a comparable phenotype. Owing to the position of the protein deletion just N-terminal of the zona pellucida (ZP) domain of α-tectorin, it is likely that the deletion of 37 amino acids may affect the proteolytic processing, structure and/or function of this domain, which results in a clinical phenotype comparable to that of missense mutations in the ZP domain. In addition, this is the first report of a synonymous mutation that affects an ESE and causes hereditary hearing loss.
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Acknowledgements
We gratefully acknowledge all the individuals who participated in this study and thank R Ensink, S van der Velde-Visser, C Beumer and K Voesenek for technical assistance. This study was financially supported by the European Commission FP6 Integrated Project EUROHEAR; contract number: LSHG-CT-20054-512063, by the ARHI KP6 Project; contract number: QLRT-2001-00331 and by the Heinsius Houbolt Foundation.
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Collin, R., de Heer, AM., Oostrik, J. et al. Mid-frequency DFNA8/12 hearing loss caused by a synonymous TECTA mutation that affects an exonic splice enhancer. Eur J Hum Genet 16, 1430–1436 (2008). https://doi.org/10.1038/ejhg.2008.110
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DOI: https://doi.org/10.1038/ejhg.2008.110
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