Mutations of human TMHS cause recessively inherited non-syndromic hearing loss

Shabbir, Muhammad Imran; Ahmed, Zubair M.; Khan, Shahid Y.; Riazuddin, Saima; Waryah, Ali Muhammad; Khan, Shaheen N.; Camps, Reyna D; Ghosh, Manju; Kabra, M.; Belyantseva, Inna A.; Friedman, Thomas B.; Riazuddin, Sheikh

doi:10.1136/jmg.2005.039834

Cited by 83 publications

(66 citation statements)

References 29 publications

(29 reference statements)

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“…We identified a homozygous, unique SNP in that critical region at 2,815,634 on chromosome 11 that causes a premature stop codon at residue 80 of Lhfpl5a (ENSDARG00000045023). The homolog of lhfpl5a, LHFPL5, causes nonsyndromic deafness in humans and the hurry scurry (hscy) mouse, thus making it a strong candidate (Longo-Guess et al, 2005;Shabbir et al, 2006;Longo-Guess et al, 2007). However, we could not validate this mutation by morpholino phenocopy, possibly because lhfpl5a functions at a late stage of development by which time the morpholinos have been degraded.…”

Section: Identification Of Lesions In Lmx1b Jag1b and Cdh23mentioning

confidence: 40%

“…Along with Protocadherin 15, Cdh23 has recently been identified as one of the components of the tip links of hair-cell bundles, where mechanical forces are transduced into electrical potentials (Kazmierczak et al, 2007;Sakaguchi et al, 2009). LHFPL5, the mammalian homolog of zebrafish lhfpl5a, has also been identified as a component of hair bundles (Kalay et al, 2006;Shabbir et al, 2006). The specific function of lhfpl5a in zebrafish will require further validation, such as by transgenic rescue, that is beyond the scope of this paper.…”

Section: Research Articlementioning

confidence: 99%

“…Alagille syndrome pathology also includes inner ear dysplasia (Koch et al, 2006). In contrast to syndromic phenotypes, autosomal recessive mutations in the human orthologs of both cdh23 and lhfpl5a cause nonsyndromic deafness (Bolz et al, 2001;Bork et al, 2001;Longo-Guess et al, 2005;Shabbir et al, 2006;Longo-Guess et al, 2007). Along with Protocadherin 15, Cdh23 has recently been identified as one of the components of the tip links of hair-cell bundles, where mechanical forces are transduced into electrical potentials (Kazmierczak et al, 2007;Sakaguchi et al, 2009).…”

Section: Research Articlementioning

confidence: 99%

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Rapid positional cloning of zebrafish mutations by linkage and homozygosity mapping using whole-genome sequencing

et al. 2012

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SUMMARYForward genetic screens in zebrafish have identified >9000 mutants, many of which are potential disease models. Most mutants remain molecularly uncharacterized because of the high cost, time and labor investment required for positional cloning. These costs limit the benefit of previous genetic screens and discourage future screens. Drastic improvements in DNA sequencing technology could dramatically improve the efficiency of positional cloning in zebrafish and other model organisms, but the best strategy for cloning by sequencing has yet to be established. Using four zebrafish inner ear mutants, we developed and compared two approaches for 'cloning by sequencing': one based on bulk segregant linkage (BSFseq) and one based on homozygosity mapping (HMFseq). Using BSFseq we discovered that mutations in lmx1b and jagged1b cause abnormal ear morphogenesis. With HMFseq we validated that the disruption of cdh23 abolishes the ear's sensory functions and identified a candidate lesion in lhfpl5a predicted to cause nonsyndromic deafness. The success of HMFseq shows that the high intrastrain polymorphism rate in zebrafish eliminates the need for time-consuming map crosses. Additionally, we analyzed diversity in zebrafish laboratory strains to find areas of elevated diversity and areas of fixed homozygosity, reinforcing recent findings that genome diversity is clustered. We present a database of >15 million sequence variants that provides much of this approach's power. In our four test cases, only a single candidate single nucleotide polymorphism (SNP) remained after subtracting all database SNPs from a mutant's critical region. The saturation of the common SNP database and our open source analysis pipeline MegaMapper will improve the pace at which the zebrafish community makes unique discoveries relevant to human health.

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Section: Identification Of Lesions In Lmx1b Jag1b and Cdh23mentioning

confidence: 40%

Section: Research Articlementioning

confidence: 99%

Section: Research Articlementioning

confidence: 99%

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Rapid positional cloning of zebrafish mutations by linkage and homozygosity mapping using whole-genome sequencing

et al. 2012

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“…It is thought that it is involved in morphogenesis of hair cells, and mutations in this gene may lead to vestibular dysfunction, corti injury, and anomalies in hair coils of the inner ear (47). The effect of mutations in this gene on hearing loss was defined in mice for the first time and later by Shabbir et al (48) in subsequent studies in two families including one from Pakistan and one from India.…”

Section: Variabilities Found In Patients Who Were Evaluated Using Thementioning

confidence: 99%

Research of genetic bases of hereditary non-syndromic hearing loss

et al. 2017

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Aim: Hearing loss is the most common sensory disorder that affects approximately one per 1000 live births. With this project, we aimed to identify gene variants that were common causes of hearing loss in Turkey to contribute to the planning of genetic screening programs for hearing loss, as well as to improve genetic counseling to affected families. Material and Methods: Twenty-one families with at least two affected individuals and parental consanguinity who presented with non-syndromic severe-to-profound sensorineural hearing loss were included in this study. We first screened for mutations in GJB2 and mitochondrial DNA 12S RNA genes. Subsequently, we genotyped the TMIE c. [250C>T] mutation in TMIE in one family. A homozygous region with SNP genotypes was detected with the OTOF gene in one family, the TMPRSS3 gene in another family, and also a homozygous region was detected with TMHS, OTOF, and TMPRSS3 genes in another family. Conclusions: Further research will be required to determine the genetic bases of hearing loss in families with non-syndromic hearing loss.

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“…The linkers between the lower end of the tip link and the dense material at the top of the actin cytoskeleton that have been reported in a number of studies (Osborne et al, 1988;Kachar et al, 2000;Furness et al, 2008) might allow the tip link to interact with the MET channels or might simply anchor the channels and/or the tip link to the lower electron-dense patch. Recent studies of a stereociliary tetraspan protein (tetraspan membrane protein of hair cell stereocilia, or THMS), mutations in which cause deafness in humans (Shabbir et al, 2006) and defects in tip-link development and transduction in mice, suggest that this protein couples PCDH15 to the channel (Box 2; Xiong et al, 2012). THMS appears to bind preferentially with the transmembrane domain and a conserved membrane proximal domain on the cytoplasmic side of PCDH15 so that it could occupy the region between the latter and the channel.…”

Section: Tip Linksmentioning

confidence: 99%

The composition and role of cross links in mechanoelectrical transduction in vertebrate sensory hair cells

Hackney

Furness

2013

Journal of Cell Science

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SummaryThe key components of acousticolateralis systems (lateral line, hearing and balance) are sensory hair cells. At their apex, these cells have a bundle of specialized cellular protrusions, which are modified actin-containing microvilli, connected together by extracellular filaments called cross links. Stereociliary deflections open nonselective cation channels allowing ions from the extracellular environment into the cell, a process called mechanoelectrical transduction. This produces a receptor potential that causes the release of the excitatory neurotransmitter glutamate onto the terminals of the sensory nerve fibres, which connect to the cell base, causing nerve signals to be sent to the brain. Identification of the cellular mechanisms underlying mechanoelectrical transduction and of some of the proteins involved has been assisted by research into the genetics of deafness, molecular biology and mechanical measurements of function. It is thought that one type of cross link, the tip link, is composed of cadherin 23 and protocadherin 15, and gates the transduction channel when the bundle is deflected. Another type of link, called lateral (or horizontal) links, maintains optimal bundle cohesion and stiffness for transduction. This Commentary summarizes the information currently available about the structure, function and composition of the links and how they might be relevant to human hearing impairment.

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Mutations of human TMHS cause recessively inherited non-syndromic hearing loss

Abstract: These findings establish the importance of TMHS for normal sound transduction in humans.

Cited by 83 publications

References 29 publications

Rapid positional cloning of zebrafish mutations by linkage and homozygosity mapping using whole-genome sequencing

Rapid positional cloning of zebrafish mutations by linkage and homozygosity mapping using whole-genome sequencing

Research of genetic bases of hereditary non-syndromic hearing loss

The composition and role of cross links in mechanoelectrical transduction in vertebrate sensory hair cells

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