A Novel <b><i>MYO6</i></b> Splice Site Mutation Causes Autosomal Dominant Sensorineural Hearing Loss Type DFNA22 with a Favourable Outcome after Cochlear Implantation

Abstract

Mutations in MYO6 encoding an atypical myosin motor protein important for inner ear hair cell function have been associated with autosomal recessive (DFNB37) and autosomal dominant (DFNA22) types of hearing loss in a few families worldwide. After genome-wide linkage analysis, we identified a novel MYO6 mutation at the splice acceptor site of exon 7 (c.554-1G>A) in an extended German family with autosomal dominant postlingual non-syndromic hearing impairment. Analysis of blood-derived cDNA revealed different aberrantly spliced mRNAs caused by the mutation, which are predicted to severely interfere with protein function. Two of the family members underwent cochlear implantation at ages 53 and 65. Here, we present detailed clinical data of this family which suggest a favourable outcome of cochlear implantation in hearing-impaired individuals with a MYO6 mutation.

Exome Sequencing Identifies a Novel Frameshift Mutation ofMYO6as the Cause of Autosomal Dominant Nonsyndromic Hearing Loss in a Chinese Family

“…χ 2 tests in pairwise comparisons showed no significant differences ( P > 0.1) for all except the Italian family (Melchionda et al., ) in which HL was caused by a missense mutation at the motor domain. Comparison to a recently reported German family (Volk et al., ) is difficult, because only six patients with the most prominent phenotypes were shown. However, the data seemed to suggest that a truncation at the motor domain could lead to early onset ages and severe HL levels.…”

“… † The resulting protein change is predicted assuming exon 7 skipping. Volk et al () indeed reported four possible consequences of the splicing change, most of which resulted in frameshift changes starting at p.A185.…”

“…A). Those mutations could trigger the nonsense mediated decay (NMD) mechanism to partially eliminate the mutant mRNAs (Hilgert et al., ; Volk et al., ). The remaining truncated myosin VI could not form dimers with the wild‐type protein to carry out normal functions (Sweeney & Houdusse, ).…”

“…The remaining truncated myosin VI could not form dimers with the wild‐type protein to carry out normal functions (Sweeney & Houdusse, ). Therefore, current data suggest the decreased level of myosin VI or haplo‐insufficiency as the major pathogenic mechanism for DFNA22, which was also discussed by other authors (Topsakal et al., ; Volk et al., ). In supporting this notion, Becker et al () recently described two patients with 6q14 deletion syndrome who had only one copy of the functioning MYO6 gene.…”

A Comprehensive Study on the Etiology of Patients Receiving Cochlear Implantation With Special Emphasis on Genetic Epidemiology

“…There have been fewer reports on the outcomes for CI for other genes, although some reports have described good performances in CI/EAS patients with associated SLC26A4 ( 25 , 39 ), OTOF ( 25 , 40 , 41 ) , MYO6 ( 8 , 42 ) , MYO15A ( 3 , 4 ) , TECTA ( 3 ) , CDH23 ( 2 ) , COCH ( 5 , 43 ) , MYH9 ( 44 , 45 ), and TMPRSS3 mutations ( 1 , 3 , 6 , 25 , 46 , 47 ). There have also been some reports describing poorer outcomes in patients with POU3F4 mutations, which are known to cause inner ear anomalies ( 48 – 51 ).…”