Mutations in a Novel Gene, TMIE, Are Associated with Hearing Loss Linked to the DFNB6 Locus

Naz, Sadaf; Giguère, Chantal; Kohrman, David C.; Mitchem, Kristina L.; Riazuddin, Saima; Morell, Robert J.; Ramesh, A.; Srisailpathy, Srikumari; Deshmukh, Dilip; Riazuddin, Sheikh; Griffith, Andrew J.; Friedman, Thomas B.; Smith, Richard J.H.; Wilcox, Edward R.

doi:10.1086/342193

Cited by 126 publications

(109 citation statements)

References 15 publications

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“…The mutant phenotype in zebrafish accords with the startle and balance deficits in spinner and circling mice and with the profound deafness in humans affected at the DFNB6 locus (23). Despite its obvious importance in auditory and vestibular function, the role of Tmie in mechanoelectrical transduction remains a mystery.…”

Section: Discussionmentioning

confidence: 85%

The transmembrane inner ear (Tmie) protein is essential for normal hearing and balance in the zebrafish

Gleason

Nagiel

Jamet

et al. 2009

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

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Little is known about the proteins that mediate mechanoelectrical transduction, the process by which acoustic and accelerational stimuli are transformed by hair cells of the inner ear into electrical signals. In our search for molecules involved in mechanotransduction, we discovered a line of deaf and uncoordinated zebrafish with defective hair-cell function. The hair cells of mutant larvae fail to incorporate fluorophores that normally traverse the transduction channels and their ears lack microphonic potentials in response to vibratory stimuli. Hair cells in the posterior lateral lines of mutants contain numerous lysosomes and have short, disordered hair bundles. Their stereocilia lack two components of the transduction apparatus, tip links and insertional plaques. Positional cloning revealed an early frameshift mutation in tmie, the zebrafish ortholog of the mammalian gene transmembrane inner ear. The mutant line therefore affords us an opportunity to investigate the role of the corresponding protein in mechanoelectrical transduction.auditory system ͉ hair cell ͉ lateral line ͉ mechanoelectrical transduction ͉ vestibular system T he vertebrate inner ear is a complex organ that houses the delicate mechanoreceptors for hearing and balance known as hair cells. Situated at the apical surface of each hair cell is an array of height-ordered stereocilia called the hair bundle. This mechanically sensitive organelle responds in a directiondependent manner to displacements caused by sound and acceleration (1). Deflection of the hair bundle toward its tall edge increases the open probability of transduction channels residing at the stereociliary tips, allowing a depolarizing inward current of cations from the surrounding endolymph. Bundle movement in the opposite direction has the opposite effect, hyperpolarizing the hair cell. The conversion of acoustic and accelerational stimuli into electrical signals that are transmitted to the auditory nerve and subsequently to the brain is known as mechanoelectrical transduction.Although we have a basic understanding of the biophysical and electrophysiological events that initiate hearing, we know much less about the molecules involved. The difficulty in identifying these components stems from the paucity of sensory tissue in the inner ear, which frustrates biochemical purification and traditional molecular-biological assays. Genetic investigation has therefore largely replaced these approaches as the preferred strategy for identifying proteins important in hearing (2).The zebrafish has proven useful for this purpose (3). The internal ear of the zebrafish, which is anatomically and functionally similar to those of other vertebrates (4), undergoes rapid development and is readily accessible for observation and manipulation owing to its optical transparency. The zebrafish possesses an additional feature useful for hair-cell investigations, the lateral-line system. This apparatus, which comprises a series of hair-cell clusters termed neuromasts distributed over the body surface, is u...

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Section: Discussionmentioning

confidence: 85%

The transmembrane inner ear (Tmie) protein is essential for normal hearing and balance in the zebrafish

Gleason

Nagiel

Jamet

et al. 2009

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

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“…Two Pakistani families had a previously published variant, c.241C>T (p.R81C) [3], which occurs at a highly conserved cytoplasmic amino acid residue (Table 2). Two other families possess novel sequence variants.…”

Section: Resultsmentioning

confidence: 99%

“…Four TMIE sequence variants that were identified in a previous study [3] were not found in the families that are reported here but were also examined in terms of conservation and occurrence of amino acid residues at functional sites (Table 4). Three missense changes at arginine residues, including the known variant p.R81C, were predicted to occur within the intracellular domain at the C-terminal tail.…”

Section: Resultsmentioning

confidence: 99%

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Novel sequence variants in the TMIE gene in families with autosomal recessive nonsyndromic hearing impairment

et al. 2005

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To date, 37 genes have been identified for nonsyndromic hearing impairment (NSHI). Identifying the functional sequence variants within these genes and knowing their population-specific frequencies is of public health value, in particular for genetic screening for NSHI. To determine putatively functional sequence variants in the transmembrane inner ear (TMIE) gene in Pakistani and Jordanian families with autosomal recessive (AR) NSHI, four Jordanian and 168 Pakistani families with ARNSHI that is not due to GJB2 (CX26) were submitted to a genome scan. Twopoint and multipoint parametric linkage analyses were performed, and families with logarithmic odds (LOD) scores of 1.0 or greater within the TMIE region underwent further DNA sequencing. The evolutionary conservation and location in predicted protein domains of amino acid residues where sequence variants occurred were studied to elucidate the possible effects of these sequence variants on function. Of seven families that were screened for TMIE, putatively functional sequence variants were found to segregate with hearing impairment in four families but were not seen in not less than 110 ethnically matched control chromosomes. The previously reported c. 241C>T (p.R81C) variant was observed in two Pakistani families. Two novel variants, c.92A>G (p.E31G) and the splice site mutation c.212-2A>C, were identified in one Pakistani and one Jordanian family, respectively. The c.92A>G (p.E31G) variant occurred at a residue that is conserved in the mouse and is predicted to be extracellular. Conservation and potential functionality of previously published mutations were also examined. The prevalence of functional TMIE variants in Pakistani families is 1.7% [95% confidence interval (CI) 0.3-4.8]. Further studies on the spectrum, prevalence rates, and functional effect of sequence variants in the TMIE gene in other populations should demonstrate the true importance of this gene as a cause of hearing impairment.

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“…This protein was only recently discovered (1997) and appears to contribute to intercellular gap junctions [13]. Connexin 26 gene also known as CX26, DFNA3, DFNB1 or GJB2, is a protein that forms channels to regulate the passage of potassium ions in and out of the cells of the cochlea.…”

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confidence: 99%

Preimplantation Genetic Diagnosis: Its Role in Prevention of Deafness

Taneja¹

2014

Indian J Otolaryngol Head Neck Surg

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Deafness is a global problem. In India deafness ranges from 4 % in urban to 11 % in rural and slum areas, out of which 50 % is conductive hearing loss hence curable. Genetic transmission accounts for 50 % of the cases of congenital deafness, and of these, around 30 % are syndromic and 70 % are non-syndromic. Genetic counseling is going to make aware the parents of all appropriate treatments. Preimplantation genetic diagnosis can help to have a baby free from genetic deafness. Procedure is almost safe, harmless, non-invasive and ethically acceptable. While Amniocentesis is a non-invasive method, prenatal genetic testing through Chorionic villous sampling is invasive. The connexin 26 (CX26W 24X) mutations are the most common cause of non-syndromic hearing loss and easy to identify by polymerase chain reaction. There is always co-morbidity after cochlear implantation and the person remains handicapped while baby after PGD shall be having healthy normal life and person prone to environmental factors may be counseled and guided to prevent deafness in next generation. Public must be made aware of noise pollution, tobacco toxicity and consanguinity. The Obstetrician and Pediatrician apart from ENT surgeon should be involved to prevent antenatal or neonatal deafness.Keywords Sensorineural deafness Á Preimplantation Á Genetic diagnosis Á National deafness programme Hearing loss is the most common sensory impairment known to man. On an average 6.3 % of the Indian population suffers from hearing loss which ranges from 4 % in urban to 11 % in rural and slum areas. For screening, preventing, counseling and curing deafness, it can be divided into two groups-conductive and sensorineural deafness. Conductive hearing loss is a mechanical defect in sound conduction from pinna through the external auditory canal, tympanic membrane, middle ear up to the annular ligament at stapedeal foot plate (Otosclerosis) [1].Sensorineural hearing loss is most commonly due to the involvement of sensory hair cells of the cochlea or sometimes of the auditory nerve or processing centre in the brain. About 50 % of the patients with sensorineural deafness are congenitally deaf. Genetic transmission accounts for 50 % of the cases of congenital (hereditary) deafness-most due to single gene mutations-and at least 90 % are inherited as Autosomal recessive traits. Of these, around 30 % are syndromic and 70 % are non-syndromic.

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Mutations in a Novel Gene, TMIE, Are Associated with Hearing Loss Linked to the DFNB6 Locus

Cited by 126 publications

References 15 publications

The transmembrane inner ear (Tmie) protein is essential for normal hearing and balance in the zebrafish

The transmembrane inner ear (Tmie) protein is essential for normal hearing and balance in the zebrafish

Novel sequence variants in the TMIE gene in families with autosomal recessive nonsyndromic hearing impairment

Preimplantation Genetic Diagnosis: Its Role in Prevention of Deafness

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