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Hiroshi Nakanishi, Kiyoto Kurima, Bifeng Pan, Philine Wangemann, Tracy S Fitzgerald, Gwenaëlle S Géléoc, Jeffrey R Holt, Andrew J Griffith
Mouse Tmc1 and Tmc2 are required for sensory transduction in cochlear and vestibular hair cells. Homozygous Tmc1∆/∆ mice are deaf, Tmc2∆/∆ mice have normal hearing, and double homozygous Tmc1∆/∆ ; Tmc2∆/∆ mice have deafness and profound vestibular dysfunction. These phenotypes are consistent with their different spatiotemporal expression patterns. Tmc1 expression is persistent in cochlear and vestibular hair cells, whereas Tmc2 expression is transient in cochlear hair cells but persistent in vestibular hair cells...
August 14, 2018: Scientific Reports
Christopher L Cunningham, Ulrich Müller
Cochlear hair cells employ mechanically gated ion channels located in stereocilia that open in response to sound wave-induced motion of the basilar membrane, converting mechanical stimulation to graded changes in hair cell membrane potential. Membrane potential changes in hair cells cause neurotransmitter release from hair cells that initiate electrical signals in the nerve terminals of afferent fibers from spiral ganglion neurons. These signals are then propagated within the central nervous system (CNS) to mediate the sensation of hearing...
August 6, 2018: Cold Spring Harbor Perspectives in Medicine
Xiang Liu, Mengmeng Zhao, Yi Xie, Ping Li, Oumei Wang, Bingxin Zhou, Linlin Yang, Yao Nie, Lin Cheng, Xicheng Song, Changzhu Jin, Fengchan Han
Fascin2 (FSCN2) is an actin cross-linking protein that is mainly localized in retinas and in the stereocilia of hair cells. Earlier studies showed that a deletion mutation in human FASCIN2 ( FSCN2 ) gene could cause autosomal dominant retinitis pigmentosa. Recent studies have indicated that a missense mutation in mouse Fscn2 gene (R109H) can contribute to the early onset of hearing loss in DBA/2J mice. To explore the function of the gene, Fscn2 was knocked out using TALEN (transcription activator-like effector nucleases) on the C57BL/6J background...
August 6, 2018: G3: Genes—Genomes—Genetics
Akira Honda, Tomoko Kita, Shri Vidhya Seshadri, Kazuyo Misaki, Zamal Ahmed, John E Ladbury, Guy P Richardson, Shigenobu Yonemura, Raj K Ladher
The mechanosensory hair cells of the inner ear are required for hearing and balance and have a distinctive apical structure, the hair bundle, that converts mechanical stimuli into electrical signals. This structure comprises a single cilium, the kinocilium, lying adjacent to an ensemble of actin-based projections known as stereocilia. Hair bundle polarity depends on kinociliary protocadherin-15 (Pcdh15) localization. Protocadherin-15 is found only in hair-cell kinocilia, and is not localized to the primary cilia of adjacent supporting cells...
August 14, 2018: Proceedings of the National Academy of Sciences of the United States of America
Jae Hyun Jung, Miryeong Kim, Seung Jae Lee, Eunsang Lee, Se A Lee, Jong Dae Lee, Ji Ho Choi, Bo Gyung Kim
OBJECTIVES: To our knowledge, the influence of sleep deprivation on hearing levels has yet to be assessed in animals. Therefore, we evaluated whether auditory function was affected by sleep deprivation in rats. METHODS: Male Wistar rats (aged 9 weeks, weighing 300-400 g) were used for the study and were randomly assigned to a control (n = 15) or sleep deprivation group (n = 12). Hearing levels were evaluated at baseline and 9 days after sleep deprivation using auditory evoked brainstem responses (ABRs) and distortion product otoacoustic emission (DPOAE) measurements...
September 2018: International Journal of Pediatric Otorhinolaryngology
Florent Delhommel, Florence Cordier, Frederick Saul, Lucas Chataigner, Ahmed Haouz, Nicolas Wolff
Whirlin is a protein essential to sensory neurons. Its defects are responsible for non-syndromic deafness or for the Usher syndrome, a condition associating congenital deafness and progressive blindness. This large multidomain scaffolding protein is expressed in three isoforms with different functions and localizations in stereocilia bundles of hearing hair cells or in the connector cilia of photoreceptor cells. The HHD2 domain of whirlin is the only domain shared by all isoforms, but its function remains unknown...
July 27, 2018: FEBS Journal
Isabelle Schrauwen, Imen Chakchouk, Anushree Acharya, Khurram Liaqat, Irfanullah, Deborah A Nickerson, Michael J Bamshad, Khadim Shah, Wasim Ahmad, Suzanne M Leal
BACKGROUND: Digenic inheritance is the simplest model of oligenic disease. It can be observed when there is a strong epistatic interaction between two loci. For both syndromic and non-syndromic hearing impairment, several forms of digenic inheritance have been reported. METHODS: We performed exome sequencing in a Pakistani family with profound non-syndromic hereditary hearing impairment to identify the genetic cause of disease. RESULTS: We found that this family displays digenic inheritance for two trans heterozygous missense mutations, one in PCDH15 [p...
July 20, 2018: BMC Medical Genetics
Xiaobai Patrinostro, Pallabi Roy, Angus Lindsay, Christopher M Chamberlain, Lauren J Sundby, Colby G Starker, Daniel F Voytas, James M Ervasti, Benjamin J Perrin
The highly similar cytoplasmic β- and γ-actins differ by only four functionally similar amino acids, yet previous in vitro and in vivo data suggest that they support unique functions due to striking phenotypic differences between Actb and Actg1 null mouse and cell models. To determine whether the four amino acid variances were responsible for the functional differences between cytoplasmic actins, we gene edited the endogenous mouse Actb locus to translate γ-actin protein. The resulting mice and primary embryonic fibroblasts completely lacked β-actin protein, but were viable and did not present with the most overt and severe cell and organismal phenotypes observed with gene knockout...
July 31, 2018: Proceedings of the National Academy of Sciences of the United States of America
Weiming Yan, Pan Long, Tao Chen, Wei Liu, Lu Yao, Ze Ren, Xiangqian Li, Jiancong Wang, Junhui Xue, Ye Tao, Lei Zhang, Zuoming Zhang
BACKGROUND/AIMS: Our laboratory discovered a Kunming mouse with enormous electroretinogram (ERG) defects. Its auditory brainstem response (ABR) threshold was significantly elevated and closely resembled the features of Usher syndrome (USH). This study sought to cross these USH-like mice (named KMush/ush mice) with CBA/CaJ mice to establish recombinant inbred strains and identify their phenotypes and genotypes. METHODS: KMush/ush mice were crossed with CBA/CaJ mice to establish inbred strains by sibling mating...
2018: Cellular Physiology and Biochemistry
Sandra Beer-Hammer, Sze Chim Lee, Stephanie A Mauriac, Veronika Leiss, Isabel A M Groh, Ana Novakovic, Roland P Piekorz, Kirsten Bucher, Chengfang Chen, Kun Ni, Wibke Singer, Csaba Harasztosi, Thomas Schimmang, Ulrike Zimmermann, Klaus Pfeffer, Lutz Birnbaumer, Andrew Forge, Mireille Montcouquiol, Marlies Knipper, Bernd Nürnberg, Lukas Rüttiger
BACKGROUND/AIMS: From invertebrates to mammals, Gαi proteins act together with their common binding partner Gpsm2 to govern cell polarization and planar organization in virtually any polarized cell. Recently, we demonstrated that Gαi3-deficiency in pre-hearing murine cochleae pointed to a role of Gαi3 for asymmetric migration of the kinocilium as well as the orientation and shape of the stereociliary ("hair") bundle, a requirement for the progression of mature hearing. We found that the lack of Gαi3 impairs stereociliary elongation and hair bundle shape in high-frequency cochlear regions, linked to elevated hearing thresholds for high-frequency sound...
2018: Cellular Physiology and Biochemistry
Erin E Baschal, Elizabeth A Terhune, Cambria I Wethey, Robin M Baschal, Kandice D Robinson, Melissa T Cuevas, Shreyash Pradhan, Brittan S Sutphin, Matthew R G Taylor, Katherine Gowan, Chad G Pearson, Lee A Niswander, Kenneth L Jones, Nancy H Miller
Idiopathic scoliosis (IS) is a structural lateral spinal curvature of ≥10° that affects up to 3% of otherwise healthy children and can lead to life-long problems in severe cases. It is well-established that IS is a genetic disorder. Previous studies have identified genes that may contribute to the IS phenotype, but the overall genetic etiology of IS is not well understood. We used exome sequencing to study five multigenerational families with IS. Bioinformatic analyses identified unique and low frequency variants (minor allele frequency ≤5%) that were present in all sequenced members of the family...
July 31, 2018: G3: Genes—Genomes—Genetics
Li-Yih Lin, Ya-Hsin Yeh, Giun-Yi Hung, Chia-Hao Lin, Pung-Pung Hwang, Jiun-Lin Horng
The calcium-sensing receptor (CaSR) is an extracellular Ca2+ sensor that plays a critical role in maintaining Ca2+ homeostasis in several organs, including the parathyroid gland and kidneys. In this study, through in situ hybridization, the expression of CaSR mRNA was found in the neuromasts of zebrafish larvae. Immunohistochemistry further demonstrated that the CaSR protein was present in neuromast hair cell stereocilia and basolateral membranes. Based on the expression and subcellular localization of the CaSR in hair cells, we hypothesized that the CaSR is expressed in zebrafish lateral-line hair cells to regulate mechanotransducer (MET)-channel-mediated Ca2+ entry...
2018: Frontiers in Physiology
Vitor G L Dantas, Manmeet H Raval, Angela Ballesteros, Runjia Cui, Laura K Gunther, Guilherme L Yamamoto, Leandro Ucela Alves, André Silva Bueno, Karina Lezirovitz, Sulene Pirana, Beatriz C A Mendes, Christopher M Yengo, Bechara Kachar, Regina C Mingroni-Netto
Whole-exome sequencing of samples from affected members of two unrelated families with late-onset non-syndromic hearing loss revealed a novel mutation (c.2090 T > G; NM_017433) in MYO3A. The mutation was confirmed in 36 affected individuals, showing autosomal dominant inheritance. The mutation alters a single residue (L697W or p.Leu697Trp) in the motor domain of the stereocilia protein MYO3A, leading to a reduction in ATPase activity, motility, and an increase in actin affinity. MYO3A-L697W showed reduced filopodial actin protrusion initiation in COS7 cells, and a predominant tipward accumulation at filopodia and stereocilia when coexpressed with wild-type MYO3A and espin-1, an actin-regulatory MYO3A cargo...
June 7, 2018: Scientific Reports
Pallabi Roy, Benjamin J Perrin
Stereocilia are mechanosensitive protrusions on the surfaces of sensory hair cells in the inner ear that detect sound, gravity, and head movement. Their cores are composed of parallel actin filaments that are cross-linked and stabilized by several actin-binding proteins, including fascin-2, plastin-1, espin, and XIRP2. The actin filaments are the most stable known, with actin turnover primarily occurring at the stereocilia tips. While stereocilia actin dynamics has been well studied, little is known about the behavior of the actin cross-linking proteins, which are the most abundant type of protein in stereocilia after actin and are critical for stereocilia morphogenesis and maintenance...
August 1, 2018: Molecular Biology of the Cell
Steven Lien, J David Dickman
The increased use of close range explosives has led to a higher incidence of exposure to blast-related head trauma. Exposure to primary blast waves is a significant cause of morbidity and mortality. Active service members and civilians who have experienced blast waves report high rates of vestibular dysfunction, such as vertigo, oscillopsia, imbalance, and dizziness. Accumulating evidence suggests that exposure to blast-wave trauma produces damage to both the peripheral and central vestibular system; similar to previous findings that blast exposure results in damage to auditory receptors...
2018: Frontiers in Neurology
Xia Wu, Shan Wang, Sen Chen, Ying-Ying Wen, Bo Liu, Wen Xie, Dan Li, Lin Liu, Xiang Huang, Yu Sun, Wei-Jia Kong
PTPRQ gene, encoding protein tyrosine phosphatase receptor Q, is essential for the normal maturation and function of hair bundle in the cochlea. Its mutations can cause the defects of stereocilia in hair cell, which lead to nonsyndromic sensorineural hearing loss. Using next-generation sequencing and Sanger sequencing method, we identified a novel compound heterozygous missense mutation, c.4472C>T p.T1491M (maternal allele) and c.1973T>C p.V658A (paternal allele), in PTPRQ gene. The two mutations are the first reported to be the cause of recessively inherited sensorineural hearing loss...
2018: Neural Plasticity
Jocelyn F Krey, Peter G Barr-Gillespie
The vertebrate hair bundle, responsible for transduction of mechanical signals into receptor potentials in sensory hair cells, is an evolutionary masterpiece. Composed of actin-filled stereocilia of precisely regulated length, width, and number, the structure of the hair bundle is optimized for sensing auditory and vestibular stimuli. Recent developments in identifying the lipids and proteins constituting the hair bundle, obtained through genetics, biochemistry, and imaging, now permit a description of the consensus composition of vestibular bundles of mouse, rat, and chick...
May 29, 2018: Cold Spring Harbor Perspectives in Medicine
Stephanie A Mauriac, Yeri E Hien, Jonathan E Bird, Steve Dos-Santos Carvalho, Ronan Peyroutou, Sze Chim Lee, Maite M Moreau, Jean-Michel Blanc, Aysegul Gezer, Chantal Medina, Olivier Thoumine, Sandra Beer-Hammer, Thomas B Friedman, Lukas Rüttiger, Andrew Forge, Bernd Nürnberg, Nathalie Sans, Mireille Montcouquiol
This corrects the article DOI: 10.1038/ncomms14907.
May 25, 2018: Nature Communications
Inger Marie Skogseid, Oddveig Røsby, Ane Konglund, James P Connelly, Bård Nedregaard, Greg Eigner Jablonski, Nadja Kvernmo, Asbjørg Stray-Pedersen, Joel C Glover
BACKGROUND: Dystonia-deafness syndrome is a well-known clinical entity, with sensorineural deafness typically manifesting earlier than dystonia. ACTB p.Arg183Trp heterozygosity has been reported in six patients to cause combined infant-onset deafness and dystonia manifesting in adolescence or young adulthood. Three of these have received beneficial pallidal stimulation. Brain imaging to assess striatal function has not been reported previously, however. Nor has a comprehensive hypothesis been presented for how the pleiotropic manifestations of this specific beta-actin gene mutation originate developmentally...
May 22, 2018: Journal of Neurodevelopmental Disorders
Xufeng Qiu, Ulrich Müller
Hair cells in the inner ear convert mechanical stimuli provided by sound waves and head movements into electrical signal. Several mechanically evoked ionic currents with different properties have been recorded in hair cells. The search for the proteins that form the underlying ion channels is still in progress. The mechanoelectrical transduction (MET) channel near the tips of stereociliary in hair cells, which is responsible for sensory transduction, has been studied most extensively. Several components of the sensory mechanotransduction machinery in stereocilia have been identified, including the multi-transmembrane proteins tetraspan membrane protein in hair cell stereocilia (TMHS)/LHFPL5, transmembrane inner ear (TMIE) and transmembrane channel-like proteins 1 and 2 (TMC1/2)...
2018: Frontiers in Cellular Neuroscience
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