A splice-site mutation and overexpression of MYO6 cause a similar phenotype in two families with autosomal dominant hearing loss

Hilgert, Nele; Topsakal, Vedat; Dinther, Joost van; Offeciers, Erwin; Heyning, Paul Van de; Camp, Guy Van

doi:10.1038/sj.ejhg.5202000

Cited by 39 publications

(41 citation statements)

References 25 publications

(21 reference statements)

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“…The missense mutation was ruled out by segregation analysis; however, the 4-bp deletion (c.862_865delACAA, p.D288DfsX17) segregated with the phenotype and was not found in 135 ethnically matched controls (270 chromosomes). Because the DFNA22 locus is not represented on AudioGene, phenotypic filtering was not applied; however, the phenotype was consistent with reported DFNA22 audioprofiles (22). Sample 8 carried two candidate variants-one mutation was ruled out by segregation analysis and the other is a known ADNSHL mutation [(DFNA2) c.842C > T, p.L281S] in KCNQ4 (18).…”

Section: Resultsmentioning

confidence: 99%

Comprehensive genetic testing for hereditary hearing loss using massively parallel sequencing

Shearer

DeLuca²,

Hildebrand³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

311

302

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The extreme genetic heterogeneity of nonsyndromic hearing loss (NSHL) makes genetic diagnosis expensive and time consuming using available methods. To assess the feasibility of targetenrichment and massively parallel sequencing technologies to interrogate all exons of all genes implicated in NSHL, we tested nine patients diagnosed with hearing loss. Solid-phase (NimbleGen) or solution-based (SureSelect) sequence capture, followed by 454 or Illumina sequencing, respectively, were compared. Sequencing reads were mapped using GSMAPPER, BFAST, and BOWTIE, and pathogenic variants were identified using a custom-variant calling and annotation pipeline (ASAP) that incorporates publicly available in silico pathogenicity prediction tools (SIFT, BLOSUM, Polyphen2, and Align-GVGD). Samples included one negative control, three positive controls (one biological replicate), and six unknowns (10 samples total), in which we genotyped 605 single nucleotide polymorphisms (SNPs) by Sanger sequencing to measure sensitivity and specificity for SureSelect-Illumina and NimbleGen-454 methods at saturating sequence coverage. Causative mutations were identified in the positive controls but not in the negative control. In five of six idiopathic hearing loss patients we identified the pathogenic mutation. Massively parallel sequencing technologies provide sensitivity, specificity, and reproducibility at levels sufficient to perform genetic diagnosis of hearing loss.deafness | genomics | Usher syndrome | diagnostics | next-generation sequencing H ereditary sensorineural hearing loss (SNHL) is the most common sensory impairment in humans (1, 2). In developed countries, two-thirds of prelingual-onset SNHL is estimated to have a genetic etiology, of which ∼70% is nonsyndromic hearing loss (NSHL). Eighty percent of NSHL is autosomal recessive nonsyndromic hearing loss (ARNSHL), ∼20% is autosomal dominant (AD), and the remainder is composed of X-linked and mitochondrial forms (1, 3). To date, 134 deafness loci have been identified, and 32 recessive (DFNB), 23 dominant (DFNA) and 2 X-linked (DFNX) genes have been cloned; 8 genes are associated with both ARNSHL and ADNSHL (4).Establishing a genetic diagnosis of NSHL is a critical component of the clinical evaluation of deaf and hard-of-hearing persons and their families. If a genetic cause of hearing loss is determined, it is possible to provide families with prognostic information, recurrence risks, and improved habilitation options. For persons diagnosed with Usher syndrome, preventative measures including sunlight protection and vitamin therapy can be implemented to minimize the rate of progression of retinitis pigmentosa (5). Most current genetic testing strategies for NSHL rely on a gene-specific Sanger sequencing approach. Because mutations in a single gene, GJB2 (DFNB1), account for up to 50% of ARNSHL in many world populations (6), this approach has changed the evaluation of patients with presumed ARNSHL. However, the mutation frequency in other genes in persons with NSHL in outbred populat...

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Section: Resultsmentioning

confidence: 99%

Comprehensive genetic testing for hereditary hearing loss using massively parallel sequencing

Shearer

DeLuca²,

Hildebrand³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

311

302

View full text Add to dashboard Cite

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“…A possible alternative explanation is that there is a regulatory sequence mutation or a position effect mutation in rsv mutant mice that affects Myo6 expression. Two reports have suggested that mutations in regulatory sequences or position effect mutations of Myo6 in the Myo6 sv allele [5] and in a family affected by autosomal dominant deafness [18]. A possible regulatory region of Myo6 was found in mice harbouring a Bmp5 se Myo6 sv allele, which shows stereocilia fusion due to a paracentric inversion caused by a break 30-220 kb upstream of Myo6 [5].…”

Section: Discussionmentioning

confidence: 99%

“…A possible regulatory region of Myo6 was found in mice harbouring a Bmp5 se Myo6 sv allele, which shows stereocilia fusion due to a paracentric inversion caused by a break 30-220 kb upstream of Myo6 [5]. Recently, it was shown by quantitative realtime PCR that mRNA expression of MYO6 in humans is elevated 1.5-to 1.8-fold in family members suffering inherited deafness compared with unaffected family members [18]. No causative mutation was found by genomic sequencing in coding exons, non-coding exons, exon-intron boundaries, UTRs, and the promoter region of MYO6 in these patients.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic and Expression Analysis of a Novel Spontaneous Myosin VI Null Mutant Mouse

et al. 2010

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Abstract:In humans, hearing is a major factor in quality of life. Mouse models are important tools for the discovery of genes responsible for genetic hearing loss, often enabling analysis of the processes that regulate the onset of deafness in humans. Thus far, at least 400 deafness mutants have been discovered in laboratory mouse populations and used in the study of deafness. Here we report the discovery of a new spontaneous recessive Rinshoken shaker/waltzer (rsv) mutant derived from our in-house C57BL/6J stock, which exhibits circling and/or head-tossing behaviour and complete lack of auditory brain response to any sound pressure. The hearing and balance phenotypes are associated with structural defects, in particular, disorganisation and fusion of stereocilia in the inner ear hair cells. Two sets of intersubspecific N 2 mice were generated for the positional cloning of the rsv mutation. The mutant locus was mapped to a 4.8-Mb region of chromosome 9, which contains myosin VI (Myo6), a gene responsible for deafness in humans and Snell's waltzer mutation in mice. The rsv mutant showed reduced expressions of Myo6 mRNA and MYO6 protein in the inner ear. Moreover, no immunoreactivity was observed in the cochlear and vestibular hair cells in the rsv mutant mice. We sequenced the genomic region (30,154 bp) of Myo6, including all coding exons, a non-coding exon, UTRs and the Myo6 promoter; however, no mutation was discovered in these regions. We therefore speculate that loss of MYO6 expression might cause shaker/waltzer behaviour and deafness in the rsv mutant; also, loss of MYO6 expression might be the result of mutations in an unidentified regulatory region(s) of the gene.

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“…As might be expected, the human disorders that are associated with these gene disruptions are nonlethal, often are late-onset, and are associated with relatively mild or variable phenotypes that might easily go undetected. The five genes, and their associated diseases, are CEL (maturity-onset diabetes of the young; OMIM: 609812) (Raeder et al 2006), IRAK3 (early onset asthma; OMIM: 611064) (Balaci et al 2007), KRT14 (ectodermal dysplasia syndromes; OMIM: 161000 and 125595) (Lugassy et al 2006), MYO6 (progressive hearing loss; OMIM: 606346) (Sanggaard et al 2008;Hilgert et al 2008), and RP1 (retinitis pigmentosa; OMIM: 180100) (Supplemental Table 6; Guillonneau et al 1999;Pierce et al 1999;Sullivan et al 1999). Three additional human genes with disruptive INDELs have mouse orthologs that are being used as human disease models in the hemizygous state.…”

Section: Coding Indels That Are Likely To Cause Human Phenotypesmentioning

confidence: 99%

Natural genetic variation caused by small insertions and deletions in the human genome

et al. 2011

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Human genetic variation is expected to play a central role in personalized medicine. Yet only a fraction of the natural genetic variation that is harbored by humans has been discovered to date. Here we report almost 2 million small insertions and deletions (INDELs) that range from 1 bp to 10,000 bp in length in the genomes of 79 diverse humans. These variants include 819,363 small INDELs that map to human genes. Small INDELs frequently were found in the coding exons of these genes, and several lines of evidence indicate that such variation is a major determinant of human biological diversity. Microarray-based genotyping experiments revealed several interesting observations regarding the population genetics of small INDEL variation. For example, we found that many of our INDELs had high levels of linkage disequilibrium (LD) with both HapMap SNPs and with high-scoring SNPs from genome-wide association studies. Overall, our study indicates that small INDEL variation is likely to be a key factor underlying inherited traits and diseases in humans.

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A splice-site mutation and overexpression of MYO6 cause a similar phenotype in two families with autosomal dominant hearing loss

Cited by 39 publications

References 25 publications

Comprehensive genetic testing for hereditary hearing loss using massively parallel sequencing

Comprehensive genetic testing for hereditary hearing loss using massively parallel sequencing

Phenotypic and Expression Analysis of a Novel Spontaneous Myosin VI Null Mutant Mouse

Natural genetic variation caused by small insertions and deletions in the human genome

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