title: A splice-site mutation and overexpression of MYO6 cause a similar phenotype in two families with autosomal dominant hearing loss.
abstract: Hearing loss is the most common sensory disorder, affecting 1 in 650 newborns. Linkage analysis revealed linkage to locus DFNA22 in two Belgian families 1 and 2 with autosomal dominant sensorineural hearing loss. As MYO6 has previously been reported as responsible for the hearing loss at loci DFNA22 and DFNB37, respectively, DNA sequencing of the coding region and the promoter of MYO6 was performed but this analysis did not reveal any mutations. However, only in patients of family 2, an insertion of 108 bp was identified in the mRNA of the gene. The inserted fragment was part of intron 23 and sequencing of this intron revealed a new splice-site mutation c.IVS23+2321T>G, segregating with the hearing loss in the family. The mutation causes a frameshift and a premature termination codon, but real-time PCR revealed that only 15-20% of the mRNA is degraded by nonsense-mediated decay, while the other part may give rise to an aberrant protein. In family 1, a quantitative real-time PCR experiment revealed a 1.5-1.8-fold overexpression of MYO6 in patients compared to controls. The possible presence of a gene duplication could be excluded by real-time PCR on genomic level. Most likely, the overexpression is caused by a mutation in an unidentified regulatory region of the gene. This study indicates that the inner ear hair cells are sensitive to changes in expression levels of MYO6.
authors.affiliation: Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
authors.forename: Nele
authors.initials: N
authors.lastname: Hilgert
authors.forename: Vedat
authors.initials: V
authors.lastname: Topsakal
authors.forename: Joost
authors.initials: J
authors.lastname: van Dinther
authors.forename: Erwin
authors.initials: E
authors.lastname: Offeciers
authors.forename: Paul
authors.initials: P
authors.lastname: Van de Heyning
authors.forename: Guy
authors.initials: G
authors.lastname: Van Camp
mesh_terms: D001483:Base Sequence; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D005786:Gene Expression Regulation; D005799:Genes, Dominant / Q000235:genetics*; D008040:Genetic Linkage; D015894:Genome, Human; D006198:Hair Cells, Auditory / Q000378:metabolism; D006239:Haplotypes; D034381:Hearing Loss / Q000235:genetics*; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D018995:Myosin Heavy Chains / Q000235:genetics* / Q000378:metabolism*; D010375:Pedigree; D010641:Phenotype; D022821:RNA Splice Sites / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D018076:DNA, Complementary; D022821:RNA Splice Sites; C089785:myosin VI; D018995:Myosin Heavy Chains