Novel Pathogenic Variants in the Gene Encoding Stereocilin (STRC) Causing Non-Syndromic Moderate Hearing Loss in Spanish and Argentinean Subjects.

Non-syndromic hearing impairment (NSHI) is a very heterogeneous genetic condition, involving over 130 genes. Mutations in GJB2, encoding connexin-26, are a major cause of NSHI (the DFNB1 type), but few other genes have significant epidemiological contributions. Mutations in the STRC gene result in the DFNB16 type of autosomal recessive NSHI, a common cause of moderate hearing loss. STRC is located in a tandem duplicated region that includes the STRCP1 pseudogene, and so it is prone to rearrangements causing structural variations. Firstly, we screened a cohort of 122 Spanish familial cases of non-DFNB1 NSHI with at least two affected siblings and unaffected parents, and with different degrees of hearing loss (mild to profound). Secondly, we screened a cohort of 64 Spanish sporadic non-DFNB1 cases, and a cohort of 35 Argentinean non-DFNB1 cases, all of them with moderate hearing loss. Amplification of marker D15S784, massively parallel DNA sequencing, multiplex ligation-dependent probe amplification and long-range gene-specific PCR followed by Sanger sequencing were used to search and confirm single-nucleotide variants (SNVs) and deletions involving STRC. Causative variants were found in 13 Spanish familial cases (10.7%), 5 Spanish simplex cases (7.8%) and 2 Argentinean cases (5.7%). In all, 34 deleted alleles and 6 SNVs, 5 of which are novel. All affected subjects had moderate hearing impairment. Our results further support this strong genotype-phenotype correlation and highlight the significant contribution of STRC mutations to moderate NSHI in the Spanish population.

Engineering olivocochlear inhibition to reduce acoustic trauma.

Efferent brain-stem neurons release acetylcholine to desensitize cochlear hair cells and can protect the inner ear from acoustic trauma. That protection is absent from knockout mice lacking efferent inhibition and is stronger in mice with a gain-of-function point mutation of the hair cell-specific nicotinic acetylcholine receptor. The present work uses viral transduction of gain-of-function receptors to restore acoustic prophylaxis to the knockout mice. Widespread postsynaptic expression of the transgene was visualized in excised tissue with a fluorophore-conjugated peptide toxin that binds selectively to hair cell acetylcholine receptors. Viral transduction into efferent knockout mice reduced the temporary hearing loss measured 1 day post acoustic trauma. The acoustic evoked-response waveform (auditory brain-stem response) recovered more rapidly in treated mice than in control mice. Thus, both cochlear amplification by outer hair cells (threshold shift) and afferent signaling (evoked-response amplitude) in knockout mice were protected by viral transduction of hair cell acetylcholine receptors. Gene therapy to strengthen efferent cochlear feedback could be complementary to existing and future therapies to prevent hearing loss, including ear coverings, hearing aids, single-gene repair, or small-molecule therapies.

The Remarkable Outer Hair Cell: Proceedings of a Symposium in Honour of W. E. Brownell.

In 1985, Bill Brownell and colleagues published the remarkable observation that cochlear outer hair cells (OHCs) express voltage-driven mechanical motion: electromotility. They proposed OHC electromotility as the mechanism for the elusive "cochlear amplifier" required to explain the sensitivity of mammalian hearing. The finding and hypothesis stimulated an explosion of experiments that have transformed our understanding of cochlear mechanics and physiology, the evolution of hair cell structure and function, and audiology. Here, we bring together examples of current research that illustrate the continuing impact of the discovery of OHC electromotility.

Gap-junctional channel and hemichannel activity of two recently identified connexin 26 mutants associated with deafness.

Gap-junction channels (GJCs) are formed by head-to-head association of two hemichannels (HCs, connexin hexamers). HCs and GJCs are permeable to ions and hydrophilic molecules of up to Mr ~1 kDa. Hearing impairment of genetic origin is common, and mutations of connexin 26 (Cx26) are its major cause. We recently identified two novel Cx26 mutations in hearing-impaired subjects, L10P and G109V. L10P forms functional GJCs with slightly altered voltage dependence and HCs with decrease ATP/cationic dye selectivity. G109V does not form functional GJCs, but forms functional HCs with enhanced extracellular Ca(2+) sensitivity and subtle alterations in voltage dependence and ATP/cationic dye selectivity. Deafness associated with G109V could result from decreased GJCs activity, whereas deafness associated to L10P may have a more complex mechanism that involves changes in HC permeability.

Tinnitus: network pathophysiology-network pharmacology.

Tinnitus, the phantom perception of sound, is a prevalent disorder. One in 10 adults has clinically significant subjective tinnitus, and for one in 100, tinnitus severely affects their quality of life. Despite the significant unmet clinical need for a safe and effective drug targeting tinnitus relief, there is currently not a single Food and Drug Administration (FDA)-approved drug on the market. The search for drugs that target tinnitus is hampered by the lack of a deep knowledge of the underlying neural substrates of this pathology. Recent studies are increasingly demonstrating that, as described for other central nervous system (CNS) disorders, tinnitus is a pathology of brain networks. The application of graph theoretical analysis to brain networks has recently provided new information concerning their topology, their robustness and their vulnerability to attacks. Moreover, the philosophy behind drug design and pharmacotherapy in CNS pathologies is changing from that of "magic bullets" that target individual chemoreceptors or "disease-causing genes" into that of "magic shotguns," "promiscuous" or "dirty drugs" that target "disease-causing networks," also known as network pharmacology. In the present work we provide some insight into how this knowledge could be applied to tinnitus pathophysiology and pharmacotherapy.

Pharmacological approaches to the treatment of tinnitus.

Tinnitus is the conscious perception of a phantom sound in the absence of an external source. For 1 in 100 of the general population, the condition severely affects quality of life. In spite of the fact that the market for a drug indicated for tinnitus relief is huge, there are still no FDA-approved drugs, and the quest for a tinnitus-targeted compound faces important challenges. A wide variety of drugs have been used off-label to treat tinnitus sufferers, with limited but significant effects in subsets of patients. If the compounds being developed at present by the pharmaceutical industry finally reach the market, they will establish a turning point in the treatment of this pathology.

Inhibition of the alpha9alpha10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-D-aspartate receptors.

In this study we report the effects of neramexane, a novel amino-alkyl-cyclohexane derivative that is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist, on recombinant rat alpha9alpha10 nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes. We compared its effects with those of memantine, a well-studied pore blocker of NMDA receptors, currently used in therapeutics for the treatment of Alzheimer's disease. Our results indicate that both compounds block acetylcholine-evoked responses at micromolar concentrations with a rank order of potency of neramexane>memantine, P<0.05. Block by neramexane of acetylcholine responses was not overcome at high concentrations of the agonist, indicative of a non-competitive inhibition. The lack of interaction of neramexane with the ligand binding domain was confirmed by radioligand binding experiments in transfected tsA201 cells. Moreover, block did not involve an increase in desensitization kinetics, it was independent of the resting potential of the membrane at low concentrations of neramexane and slightly voltage-dependent at concentrations higher than 1 microM. Finally, clinically-relevant concentrations of neramexane blocked native alpha9alpha10-containing nicotinic acetylcholine receptors of rat inner hair cells, thus demonstrating a possible in vivo relevance in potentially unexplored therapeutic areas.

Effect of acute exposure to reduced atmospheric pressures on body weight, food intake and body composition of growing rats

Ratas macho jóvenes fueron expuestas a alturas simuladas de 1 850, 2 900, 4 100, 5 450 ó 7 100 m en una cámara hipobárica con el objeto de determinar los efectos de la altura sobre la ganancia de peso corporal y la ingesta de alimentos en función del tiempo de exposición. Ratas hembra fueron expuestas a altura simulada de 7 100 m durante 24 h con el objeto de determinar el efecto de la altura sobre la composición corporal. Los resultados obtenidos indican que en ratas jóvenes expuestas a alturas simuladas en forma aguda 1) la pérdida inicial de peso y la depresión de la velocidad de crecimiento corporal, por un lado, y la reducción de la ingesta de alimento, por el otro, están relacionadas con el grado de altura; los parámetros citadosno son afectados a alturas inferiores a 1 850 m; 2) la pérdida inicial de peso no es debida únicamente a la reducción de la ingesta alimenticia, siendo la pérdida adicional atribuida al "stress" de la hipoxia; 3) la pérdida de peso ocorre sin que se observen alteraciones marcadas de la composición corporal, aunque se manifiesta una tendencia a la dehidratación; 4) los cambios observados en la composición corporal son el reflejo de la hipofagia inducida por la altura (AU)

Effect of acute exposure to reduced atmospheric pressures on body weight, food intake and body composition of growing rats

Ratas macho jóvenes fueron expuestas a alturas simuladas de 1 850, 2 900, 4 100, 5 450 ó 7 100 m en una cámara hipobárica con el objeto de determinar los efectos de la altura sobre la ganancia de peso corporal y la ingesta de alimentos en función del tiempo de exposición. Ratas hembra fueron expuestas a altura simulada de 7 100 m durante 24 h con el objeto de determinar el efecto de la altura sobre la composición corporal. Los resultados obtenidos indican que en ratas jóvenes expuestas a alturas simuladas en forma aguda 1) la pérdida inicial de peso y la depresión de la velocidad de crecimiento corporal, por un lado, y la reducción de la ingesta de alimento, por el otro, están relacionadas con el grado de altura; los parámetros citadosno son afectados a alturas inferiores a 1 850 m; 2) la pérdida inicial de peso no es debida únicamente a la reducción de la ingesta alimenticia, siendo la pérdida adicional atribuida al "stress" de la hipoxia; 3) la pérdida de peso ocorre sin que se observen alteraciones marcadas de la composición corporal, aunque se manifiesta una tendencia a la dehidratación; 4) los cambios observados en la composición corporal son el reflejo de la hipofagia inducida por la altura