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In this study, a five-generation Chinese family (family F013) with progressive autosomal dominant hearing loss was mapped to a critical region spanning 28.54 Mb on chromosome 9q31.3-q34.3 by linkage analysis, which was a novel DFNA locus, assigned as DFNA56. In this interval, there were 398 annotated genes. Then, whole exome sequencing was applied in three patients and one normal individual from this family. Six single nucleotide variants and two indels were found co-segregated with the phenotypes. Then using mass spectrum (Sequenom, Inc.) to rank the eight sites, we found only the TNC gene be co-segregated with hearing loss in 53 subjects of F013. And this missense mutation (c.5317G>A, p.V1773M ) of TNC located exactly in the critical linked interval. Further screening to the coding region of this gene in 587 subjects with nonsyndromic hearing loss (NSHL) found a second missense mutation, c.5368A>T (p. T1796S), co-segregating with phenotype in the other family. These two mutations located in the conserved region of TNC and were absent in the 387 normal hearing individuals of matched geographical ancestry. Functional effects of the two mutations were predicted using SIFT and both mutations were deleterious. All these results supported that TNC may be the causal gene for the hearing loss inherited in these families. TNC encodes tenascin-C, a member of the extracellular matrix (ECM), is present in the basilar membrane (BM), and the osseous spiral lamina of the cochlea. It plays an important role in cochlear development. The up-regulated expression of TNC gene in tissue repair and neural regeneration was seen in human and zebrafish, and in sensory receptor recovery in the vestibular organ after ototoxic injury in birds. Then the absence of normal tenascin-C was supposed to cause irreversible injuries in cochlea and caused hearing loss.

Mechanoelectrical transduction (MET), the conversion of mechanical stimuli into electrical signals operated by the sensory cells of the inner ear, enables hearing and balance perception. Crucial to this process are the tip-links, oblique fibrous filaments that interconnect the actin-filled stereocilia of different rows within the hair bundle, and mechanically gate MET channels. In a recent study, we observed a complete regression of stereocilia from the short and medium but not the tall row upon the disappearance of the tip-links caused by the loss of one of their components, cadherin-23, or of one of their anchoring proteins, sans, in the auditory organs of engineered mutant mice. This indicates the existence of a coupling between the MET and F-actin polymerization machineries at the tips of the short and medium stereocilia rows in cochlear hair bundles. Here, we first present our findings in the mutant mice, and then discuss the possible effects of the tip-link tension on stereocilia F-actin polymerization, acting either directly or through Ca(2+)-dependent mechanisms that involve the gating of MET channels.

Several key properties of sound perception rest upon the pre-processing of sound by outer hair cells (OHC) in the mammalian inner ear, that is, one stage ahead of the mechanoelectrical transduction eventually achieved by inner hair cells. It has been acknowledged for two decades that OHCs mechanically amplify sound stimuli, which explains why the auditory system of mammals is sensitive enough to detect sound power levels hardly an order of magnitude above thermal noise. The fine tonotopy obse...

Texte introductif du Pr Stanislas Dehaene Un seul chiffre suffira à introduire notre sujet : 40 milliards de dollars, c’est l’ordre de grandeur du marché de la musique dans le monde. Chacun est prêt à dépenser des sommes importantes en appareils de haute fidélité, en baladeurs et en disques dont la fonction n’est, après tout, que de dispenser quelques vibrations sonores – mais des vibrations capables de nous émouvoir au plus profond de nous mêmes. Glenn Gould, pianiste mythique, expliquait q...

Introductory talk by Professor Stanislas Dehaene A single figure will suffice to introduce my subject: 40 billion dollars. That is the size of the world’s music market. Everyone is prepared to spend large sums of money on hi-fi systems, portable devices and discs whose only function is to dispense sound waves – but sound waves capable of moving us to the depths of our soul. The mythical pianist Glenn Gould explained that he could never have imagined his life without total immersion in music,...

National audience; This project has been performed in order to know DON becoming from durum wheat grain to cooked pasta as consumed and the evaluation of pasta consumer exposition to DON. DON dosage by HPLC has been validated on the various matrices (durum wheat grains, fractions resulting from pasta process, raw and cooked pasta). Four durum wheat samples, including one very contaminated by DON (> 4000 μg/kg) and three less (≤ 2000 μg/kg), were the subject of DON analyses all along the pasta process. The results show that the process of semolina industry decreases the DON contamination of 25 %. Cooking eliminates from 40 to 60 % of DON in raw pasta and the ultimate consumer is exposed to 14 % of DON quantity present in the durum wheat grains at harvest for the more contaminated wheat (7000 μg/kg). The exposure of the consumer of pasta contaminated by 500 μg/kg of DON is weak for the average of consumers, since the maximum value, which is found in the children from 3 to 5 years, is equal to 14 % of TDI (Tolerable Daily Intake).; Ce projet a porté sur le devenir du DON du grain de blé dur à la pâte alimentaire cuite, telle que consommée et l'évaluation de l'exposition du consommateur de pâtes alimentaires à DON. Il a permis de valider le dosage par HPLC de DON sur les différentes matrices concernées (grains de blé dur, fractions issus du process pastier, pâtes crues et cuites). Quatre lots de blé dur, dont un très contaminé par DON (> 4000 μg/kg) et trois moins (≤ 2000 μg/kg) ont fait l'objet d'analyses de DON tout le long du process pastier. Les résultats ont montré que les opérations de semoulerie diminuent la contamination en DON de 25 %. La cuisson élimine de 40 à 60 % du DON présent dans les pâtes crues et le consommateur final est exposé à 14 % de la quantité de DON présent sur les grains de blé dur à la récolte pour le lot le plus contaminé (7000 μg/kg). L'exposition du consommateur de pâtes alimentaires contaminées par DON à un niveau de l'ordre de 500 μg/kg est faible pour la moyenne des consommateurs puisque la valeur maximale qui est retrouvée chez les enfants de 3 à 5 ans est égale à 14 % de la DJT.

Defects in myosin VIIa, the PDZ-domain-containing protein harmonin, cadherin 23, protocadherin 15, and the putative scaffolding protein sans, underlie five genetic forms of Usher syndrome type I (USH1), the most frequent cause of hereditary deafness-blindness in humans. Mice mutants defective for any of these proteins have a severe hearing impairment and display similar inner ear phenotypes characterized by the abnormal spreading of the sensory cells' stereocilia. These are highly specialized mechanoreceptive organelles derived from microvilli, that normally form a well-structured hair bundle at the apex of inner ear sensory cells. All the USH1 proteins, except sans, have been detected in the growing stereocilia. Moreover, biochemical studies have started to unravel the multiple direct molecular interactions between USH1 proteins. In particular, harmonin can bind to the other four USH1 proteins and to F-actin. Finally, cell biology studies have provided the first insights into the functions of these proteins, and revealed that cadherin 23, and probably protocadherin 15 also, are associated with transient lateral links that interconnect growing stereocilia. These connectors play a critical role in the differentiating hair bundle., Une description phénoménologique précise de la différenciation de la touffe ciliaire des cellules sensorielles de l’oreille interne a été réalisée il y a environ 20 ans chez le poulet. Pourtant, les mécanismes cellulaires concourant à la formation de cette structure remarquablement organisée, qui assure la transformation d’un son ou d’une accélération en un signal électrique (transduction mécano-électrique), demeurent très mal connus. Récemment, par des approaches génétiques conjointes chez l’homme et la souris, cinq des protéines directement impliquées dans le syndrome de Usher de type I, un double deficit sensoriel qui concerne à la fois l’audition et la vision, ont pu être caractérisées. Ces découvertes ont d’ores et déjà permis d’identifier les liens interstéréociliaires comme des acteurs essentials de la différenciation des touffes ciliaires.