Mid-frequency DFNA8/12 hearing loss caused by a synonymous TECTA mutation that affects an exonic splice enhancer

Abstract

Autosomal dominant hearing loss is highly heterogeneous. Hearing impairment mainly involves the midfrequencies (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.5331G4A; 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 a-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 a-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.

Mutation spectrum of and founder effects affecting the PTS gene in East Asian populations

“…[22][23][24] The disruption of a consensus splice sequence is the most frequent type of splicing error mutation and leads to the skipping of exons. 22 Three such mutations, c.163+1G4A, c.186+1G4A and c.243G4A, were observed in this study.…”

“…18,25 The newly identified c.163+1G4A variant disrupts a consensus splice site sequence, which suggests that it causes a splicing error mutation. In human disease genes, there are numerous mutations in ESE control sequences that have been documented as causing aberrant exon skipping 23 or the creation of pseudoexon. 24 The c.168G4A mutation (p.V56V) was identified in a patient from southern Mainland China who also carried a single c.84-291A4G mutation.…”

Genetic causes of nonsyndromic hearing loss in Iran in comparison with other populations

“…79 Mutations of various parts of a-tectorin lead to HL at different frequencies and lead to specific genotype-phenotype correlations. 71,[80][81][82] TMC1 gene Mutations in the transmembrane cochlear-expressed gene 1 (TMC1), located on chromosome 9q13-21, can also result in both progressive autosomal dominant and autosomal recessive HL (DFNA36 and DFNB7/DFNB11). 83,84 There are eight vertebrate TMC genes on the basis of their sequence homology.…”

Progressive Sensorineural Hearing Loss and Normal Vestibular Function in a Dutch DFNB7/11 Family with a Novel Mutation in <i>TMC1</i>

“…Primer sequences are listed in online supplement table 1 (www.karger.com/doi/10.1159/000313282). Sequence analysis was performed as described before [Collin et al, 2008a] using the same primers that were used for PCR. Primer sequences are listed in online supplement table 1.…”