Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families

Shahin, Hashem; Walsh, Tom; Rayyan, Amal Abu; Lee, Ming K.; Higgins, John; Dickel, Diane E.; Lewis, Kristen; Thompson, James; Baker, Carl; Nord, Alexander; Stray, Sunday M.; Genevieve, David; Avraham, Karen B.; King, Mary Claire; Kanaan, Moien

doi:10.1038/ejhg.2009.190

Cited by 79 publications

(66 citation statements)

References 23 publications

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“…In one family with seven IBD regions, we found a relatively common, recently described deletion over the gene OTOA at 16p12.2, explaining their hearing impairment, but not the ID. 28 Identifying the causing mutation in TRAPPC9 in family MR055 Family MR055 consists of two branches (a and b). In the first branch, parents were cousins I1, and there were three affected females (two are true twins) and one healthy male.…”

Section: Methodsmentioning

confidence: 99%

Homozygosity mapping in 64 Syrian consanguineous families with non-specific intellectual disability reveals 11 novel loci and high heterogeneity

et al. 2011

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Non-specific intellectual disability of autosomal recessive inheritance (NS-ARID) represents an important fraction of severe cognitive dysfunction disorders. To date, only 10 genes have been identified, and further 24 linked-ARID loci have been reported, as well as others with suggestive linkage. To discover novel genes causing NS-ARID, we undertook genome-wide homozygosity mapping in 64 consanguineous multiplex families of Syrian descent. A total of 11 families revealed unique, significantly linked loci at 4q26-4q28 (MRT17), 6q12-q15 (MRT18), 18p11 (MRT19), 16p12-q12 (MRT20), 11p15 (MRT21), 11p13-q14 (MRT23), 6p12 (MRT24), 12q13-q15 (MRT25), 14q11-q12 (MRT26), 15q23-q26 (MRT27), and 6q26-q27 (MRT28), respectively. Loci ranged between 1.2 and 45.6 Mb in length. One family showed linkage to chromosome 8q24.3, and we identified a mutation in TRAPPC9. Our study further highlights the extreme heterogeneity of NS-ARID, and suggests that no major disease gene is to be expected, at least in this study group. Systematic analysis of large numbers of affected families, as presented here, will help discovering the genetic causes of ID.

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Section: Methodsmentioning

confidence: 99%

Homozygosity mapping in 64 Syrian consanguineous families with non-specific intellectual disability reveals 11 novel loci and high heterogeneity

et al. 2011

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“…The results also inform as to the cause of deafness in DFNB22 families. Three different recessive mutations in OTOA-a splice site mutation, a missense mutation, and a large genomic deletion-have been identified in Palestinian families as the cause of prelingual, sensorineural deafness (25,46,47). The degree of deafness of the affected individuals in two of these three families has been reported and has been described as being moderate to severe, i.e., similar or slightly more severe than the 35-to 55-dB hearing loss found in the Otoa EGFP/EGFP mouse over the 8-to 55-kHz range.…”

Section: Discussionmentioning

confidence: 99%

A mouse model for human deafness DFNB22 reveals that hearing impairment is due to a loss of inner hair cell stimulation

Lukashkin

Legan

Weddell

et al. 2012

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

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The gene causative for the human nonsyndromic recessive form of deafness DFNB22 encodes otoancorin, a 120-kDa inner ear-specific protein that is expressed on the surface of the spiral limbus in the cochlea. Gene targeting in ES cells was used to create an EGFP knock-in, otoancorin KO (Otoa EGFP/EGFP ) mouse. In the Otoa EGFP/EGFP mouse, the tectorial membrane (TM), a ribbon-like strip of ECM that is normally anchored by one edge to the spiral limbus and lies over the organ of Corti, retains its general form, and remains in close proximity to the organ of Corti, but is detached from the limbal surface. Measurements of cochlear microphonic potentials, distortion product otoacoustic emissions, and basilar membrane motion indicate that the TM remains functionally attached to the electromotile, sensorimotor outer hair cells of the organ of Corti, and that the amplification and frequency tuning of the basilar membrane responses to sounds are almost normal. The compound action potential masker tuning curves, a measure of the tuning of the sensory inner hair cells, are also sharply tuned, but the thresholds of the compound action potentials, a measure of inner hair cell sensitivity, are significantly elevated. These results indicate that the hearing loss in patients with Otoa mutations is caused by a defect in inner hair cell stimulation, and reveal the limbal attachment of the TM plays a critical role in this process.T he sensory epithelium of the cochlea, the organ of Corti ( Fig. 1), contains two types of hair cell, the purely sensory inner hair cells (IHCs) and the electromotile, sensorimotor outer hair cells (OHCs). These cells are critically positioned between two strips of ECM, the basilar membrane (BM) and the tectorial membrane (TM). Signal processing in the cochlea is initiated when sound-induced changes in fluid pressure displace the BM in the transverse direction, causing radial shearing displacements between the surface of the organ of Corti (the reticular lamina) and the overlying TM (1). The radial shear is detected by the hair bundles of the IHCs and the OHCs (2), with the stereocilia of the OHC hair bundles forming an elastic link between the organ of Corti and the overlying TM (3). Deflection of the stereocilia gates the hair cell's mechanoelectrical transducer (MET) channels, thereby initiating a MET current (4) that promotes active mechanical force production by the OHCs, which, in turn, influences mechanical interactions between the TM and the BM (5, 6). This nonlinear frequency-dependent enhancement process, which boosts the sensitivity of cochlear responses to lowlevel sounds and compresses them at high levels, is known as the cochlear amplifier (7).Whereas the hair bundles of the OHCs are imbedded into the TM and therefore directly excited by relative displacement of the undersurface of the TM and the reticular lamina, those of the IHCs are not in direct contact with the TM, and the way in which they are driven by motion of the BM remains unclear. Intracellular recordings of the receptor potent...

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“…Before this study, one MYO7A mutation was known in the Middle East population among the Palestinian Arabs for non-syndromic hearing loss. 22 Previously, mutations for a syndromic form of deafness, Usher syndrome type IB, had been identified in this gene in Israel. 44,45 Targeted MPS enabled the discovery of an additional five novel mutations in this gene among both the Israeli Jewish and the Palestinian Arab populations, suggesting that more unidentified mutations may exist.…”

Section: Discussionmentioning

confidence: 99%

“…3,[23][24][25] All known deafness-causing mutations in the Palestinian population were excluded, including mutations in CDH23, MYO7A, MYO15A, OTOF, PJVK, SLC26A4, TECTA, TMHS, TMPRSS3, OTOA, PTPRQ and GPSM2. 22,26,27 Massive parallel sequencing Capture libraries were created and MPS was performed, followed by bioinformatics analysis, as previously described. 28,29 Exons and the flanking 40 bp into the introns of 284 human deafness-associated genes were captured using the SureSelect Target Enrichment Solution (Agilent, Santa Clara, CA, USA) and sequenced on an Illumina HiSeq 2000 Analyzer (HT-Seq Unit, Technion, Haifa, Israel).…”

Section: Gene Exclusionmentioning

confidence: 99%

“…20 MYO15A mutations were discovered concomitantly in human DFNB3 families and in the shaker 2 mouse. 12,21 In the Middle Eastern Jewish and Arab populations, to date, eight mutations have been reported in myosins IIIA, 7 myosin VIIA 22 and myosin XVA. 3,22 The present study, using targeted capture and MPS, defines nine novel mutations in MYO6, MYO7A and MYO15A, doubling the number of myosin mutations present in the Middle East responsible for non-syndromic hearing loss.…”

Section: Introductionmentioning

confidence: 99%

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Novel myosin mutations for hereditary hearing loss revealed by targeted genomic capture and massively parallel sequencing

et al. 2013

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Hereditary hearing loss is genetically heterogeneous, with a large number of genes and mutations contributing to this sensory, often monogenic, disease. This number, as well as large size, precludes comprehensive genetic diagnosis of all known deafness genes. A combination of targeted genomic capture and massively parallel sequencing (MPS), also referred to as next-generation sequencing, was applied to determine the deafness-causing genes in hearing-impaired individuals from Israeli Jewish and Palestinian Arab families. Among the mutations detected, we identified nine novel mutations in the genes encoding myosin VI, myosin VIIA and myosin XVA, doubling the number of myosin mutations in the Middle East. Myosin VI mutations were identified in this population for the first time. Modeling of the mutations provided predicted mechanisms for the damage they inflict in the molecular motors, leading to impaired function and thus deafness. The myosin mutations span all regions of these molecular motors, leading to a wide range of hearing phenotypes, reinforcing the key role of this family of proteins in auditory function. This study demonstrates that multiple mutations responsible for hearing loss can be identified in a relatively straightforward manner by targeted-gene MPS technology and concludes that this is the optimal genetic diagnostic approach for identification of mutations responsible for hearing loss.

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Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families

Cited by 79 publications

References 23 publications

Homozygosity mapping in 64 Syrian consanguineous families with non-specific intellectual disability reveals 11 novel loci and high heterogeneity

Homozygosity mapping in 64 Syrian consanguineous families with non-specific intellectual disability reveals 11 novel loci and high heterogeneity

A mouse model for human deafness DFNB22 reveals that hearing impairment is due to a loss of inner hair cell stimulation

Novel myosin mutations for hereditary hearing loss revealed by targeted genomic capture and massively parallel sequencing

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