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Hearing Disorders: HELP
Articles by Andrew Forge
Based on 11 articles published since 2009
(Why 11 articles?)

Between 2009 and 2019, A. Forge wrote the following 11 articles about Hearing Disorders.
+ Citations + Abstracts
1 Review The enigmatic root cell - emerging roles contributing to fluid homeostasis within the cochlear outer sulcus. 2013

Jagger, Daniel J / Forge, Andrew. ·Centre for Auditory Research, UCL Ear Institute, University College London, 332 Gray's Inn Road, London WC1X 8EE, UK. d.jagger@ucl.ac.uk ·Hear Res · Pubmed #23151402.

ABSTRACT: Despite their curious morphology prompting numerous hypotheses of their normal function, the root cells lining the cochlear outer sulcus have long evaded physiological characterization. A growing body of evidence now suggests that they regulate the solute content of the endolymph and/or the perilymph, and may be essential in safe-guarding the global homeostasis of the cochlea. Immuno-labeling experiments have demonstrated polarized expression of key ion transport proteins, and recent electrophysiological recordings have identified specific membrane conductances. These studies have painted a clearer picture of how this unusual cell type may contribute to the maintenance of sound transduction, and how they may be central to pathological processes associated with various forms of hearing loss. This article is part of a Special Issue entitled "Annual Reviews 2013".

2 Article Defective Gpsm2/Gα 2017

Mauriac, Stephanie A / Hien, Yeri E / Bird, Jonathan E / Carvalho, Steve Dos-Santos / Peyroutou, Ronan / Lee, Sze Chim / Moreau, Maite M / Blanc, Jean-Michel / Geyser, Aysegul / Medina, Chantal / Thoumine, Olivier / Beer-Hammer, Sandra / Friedman, Thomas B / Rüttiger, Lukas / Forge, Andrew / Nürnberg, Bernd / Sans, Nathalie / Montcouquiol, Mireille. ·INSERM, Neurocentre Magendie, U1215, 146 rue Leo-Saignat, F-33077 Bordeaux, France. · Univ. Bordeaux, Neurocentre Magendie, U1215, F-33077 Bordeaux, France. · Section on Human Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, Maryland 20892, USA. · Department of Otolaryngology, Hearing Research Centre Tübingen, Molecular Physiology of Hearing, University of Tübingen, D-72076 Tübingen, Germany. · Biochemistry and Biophysics Facility of the Bordeaux Neurocampus, F-33077 Bordeaux, France. · CNRS, Interdisciplinary Institute for Neuroscience, UMR 5297, 146 rue Leo-Saignat, F-33077 Bordeaux, France. · Univ. Bordeaux, Interdisciplinary Institute for Neuroscience, UMR 5297, F-33077 Bordeaux, France. · Department of Pharmacology and Experimental Therapy and Interfaculty Center of Pharmacogenomics and Drug Research, University of Tübingen, 72074 Tubingen, Germany. · UCL Ear Institute, London WC1X 8EE, UK. ·Nat Commun · Pubmed #28387217.

ABSTRACT: Mutations in GPSM2 cause Chudley-McCullough syndrome (CMCS), an autosomal recessive neurological disorder characterized by early-onset sensorineural deafness and brain anomalies. Here, we show that mutation of the mouse orthologue of GPSM2 affects actin-rich stereocilia elongation in auditory and vestibular hair cells, causing deafness and balance defects. The G-protein subunit Gα

3 Article Disruption of SorCS2 reveals differences in the regulation of stereociliary bundle formation between hair cell types in the inner ear. 2017

Forge, Andrew / Taylor, Ruth R / Dawson, Sally J / Lovett, Michael / Jagger, Daniel J. ·UCL Ear Institute, University College London, London, United Kingdom. · National Heart and Lung Institute, Imperial College London, London, United Kingdom. ·PLoS Genet · Pubmed #28346477.

ABSTRACT: Behavioural anomalies suggesting an inner ear disorder were observed in a colony of transgenic mice. Affected animals were profoundly deaf. Severe hair bundle defects were identified in all outer and inner hair cells (OHC, IHC) in the cochlea and in hair cells of vestibular macular organs, but hair cells in cristae were essentially unaffected. Evidence suggested the disorder was likely due to gene disruption by a randomly inserted transgene construct. Whole-genome sequencing identified interruption of the SorCS2 (Sortilin-related VPS-10 domain containing protein) locus. Real-time-qPCR demonstrated disrupted expression of SorCS2 RNA in cochlear tissue from affected mice and this was confirmed by SorCS2 immuno-labelling. In all affected hair cells, stereocilia were shorter than normal, but abnormalities of bundle morphology and organisation differed between hair cell types. Bundles on OHC were grossly misshapen with significantly fewer stereocilia than normal. However, stereocilia were organised in rows of increasing height. Bundles on IHC contained significantly more stereocilia than normal with some longer stereocilia towards the centre, or with minimal height differentials. In early postnatal mice, kinocilia (primary cilia) of IHC and of OHC were initially located towards the lateral edge of the hair cell surface but often became surrounded by stereocilia as bundle shape and apical surface contour changed. In macular organs the kinocilium was positioned in the centre of the cell surface throughout maturation. There was disruption of the signalling pathway controlling intrinsic hair cell apical asymmetry. LGN and Gαi3 were largely absent, and atypical Protein Kinase C (aPKC) lost its asymmetric distribution. The results suggest that SorCS2 plays a role upstream of the intrinsic polarity pathway and that there are differences between hair cell types in the deployment of the machinery that generates a precisely organised hair bundle.

4 Article ILDR1 null mice, a model of human deafness DFNB42, show structural aberrations of tricellular tight junctions and degeneration of auditory hair cells. 2015

Morozko, Eva L / Nishio, Ayako / Ingham, Neil J / Chandra, Rashmi / Fitzgerald, Tracy / Martelletti, Elisa / Borck, Guntram / Wilson, Elizabeth / Riordan, Gavin P / Wangemann, Philine / Forge, Andrew / Steel, Karen P / Liddle, Rodger A / Friedman, Thomas B / Belyantseva, Inna A. ·National Institute on Deafness and Other Communication Disorders, Section on Human Genetics. · National Institute on Deafness and Other Communication Disorders, Molecular Biology and Genetics Section. · Wolfson Centre for Age-Related Diseases, King's College London, London SE1 1UL, UK. · Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. · National Institute on Deafness and Other Communication Disorders, Mouse Auditory Testing Core Facility, National Institutes of Health, Bethesda, MD 20892-3729, USA. · Institute of Human Genetics, University of Ulm, Ulm 89081, Germany. · Anatomy and Physiology Department, Kansas State University, Manhattan, KS 66506-5802, USA and. · Centre for Auditory Research, University College London, London WC1X 8EE, UK. · National Institute on Deafness and Other Communication Disorders, Section on Human Genetics belyants@nidcd.nih.gov. ·Hum Mol Genet · Pubmed #25217574.

ABSTRACT: In the mammalian inner ear, bicellular and tricellular tight junctions (tTJs) seal the paracellular space between epithelial cells. Tricellulin and immunoglobulin-like (Ig-like) domain containing receptor 1 (ILDR1, also referred to as angulin-2) localize to tTJs of the sensory and non-sensory epithelia in the organ of Corti and vestibular end organs. Recessive mutations of TRIC (DFNB49) encoding tricellulin and ILDR1 (DFNB42) cause human nonsyndromic deafness. However, the pathophysiology of DFNB42 deafness remains unknown. ILDR1 was recently reported to be a lipoprotein receptor mediating the secretion of the fat-stimulated cholecystokinin (CCK) hormone in the small intestine, while ILDR1 in EpH4 mouse mammary epithelial cells in vitro was shown to recruit tricellulin to tTJs. Here we show that two different mouse Ildr1 mutant alleles have early-onset severe deafness associated with a rapid degeneration of cochlear hair cells (HCs) but have a normal endocochlear potential. ILDR1 is not required for recruitment of tricellulin to tTJs in the cochlea in vivo; however, tricellulin becomes mislocalized in the inner ear sensory epithelia of ILDR1 null mice after the first postnatal week. As revealed by freeze-fracture electron microscopy, ILDR1 contributes to the ultrastructure of inner ear tTJs. Taken together, our data provide insight into the pathophysiology of human DFNB42 deafness and demonstrate that ILDR1 is crucial for normal hearing by maintaining the structural and functional integrity of tTJs, which are critical for the survival of auditory neurosensory HCs.

5 Article Absence of plastin 1 causes abnormal maintenance of hair cell stereocilia and a moderate form of hearing loss in mice. 2015

Taylor, Ruth / Bullen, Anwen / Johnson, Stuart L / Grimm-Günter, Eva-Maria / Rivero, Francisco / Marcotti, Walter / Forge, Andrew / Daudet, Nicolas. ·Centre for Auditory Research, UCL Ear Institute, University College London, London, UK. · Department of Biomedical Science, University of Sheffield, Sheffield, UK and. · Centre for Cardiovascular and Metabolic Research, The Hull York Medical School, University of Hull, Hull, UK. · Centre for Auditory Research, UCL Ear Institute, University College London, London, UK n.daudet@ucl.ac.uk. ·Hum Mol Genet · Pubmed #25124451.

ABSTRACT: Hearing relies on the mechanosensory inner and outer hair cells (OHCs) of the organ of Corti, which convert mechanical deflections of their actin-rich stereociliary bundles into electrochemical signals. Several actin-associated proteins are essential for stereocilia formation and maintenance, and their absence leads to deafness. One of the most abundant actin-bundling proteins of stereocilia is plastin 1, but its function has never been directly assessed. Here, we found that plastin 1 knock-out (Pls1 KO) mice have a moderate and progressive form of hearing loss across all frequencies. Auditory hair cells developed normally in Pls1 KO, but in young adult animals, the stereocilia of inner hair cells were reduced in width and length. The stereocilia of OHCs were comparatively less affected; however, they also showed signs of degeneration in ageing mice. The hair bundle stiffness and the acquisition of the electrophysiological properties of hair cells were unaffected by the absence of plastin 1, except for a significant change in the adaptation properties, but not the size of the mechanoelectrical transducer currents. These results show that in contrast to other actin-bundling proteins such as espin, harmonin or Eps8, plastin 1 is dispensable for the initial formation of stereocilia. However, the progressive hearing loss and morphological defects of hair cells in adult Pls1 KO mice point at a specific role for plastin 1 in the preservation of adult stereocilia and optimal hearing. Hence, mutations in the human PLS1 gene may be associated with relatively mild and progressive forms of hearing loss.

6 Article Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss. 2014

Chen, Jing / Ingham, Neil / Kelly, John / Jadeja, Shalini / Goulding, David / Pass, Johanna / Mahajan, Vinit B / Tsang, Stephen H / Nijnik, Anastasia / Jackson, Ian J / White, Jacqueline K / Forge, Andrew / Jagger, Daniel / Steel, Karen P. ·Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Wolfson Centre for Age-Related Diseases, King's College London, London, United Kingdom. · Centre for Auditory Research, UCL Ear Institute, London, United Kingdom. · MRC Human Genetics Unit, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom, and Roslin Institute, University of Edinburgh, Easter Bush, United Kingdom. · Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom. · Omics Laboratory, University of Iowa, Iowa City, Iowa, United States of America. · Edward S. Harkness Eye Institute, Columbia University, New York, New York, United States of America. · Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Department of Physiology, Complex Traits Group, McGill University, Montreal, Quebec, Canada. ·PLoS Genet · Pubmed #25356849.

ABSTRACT: Spinster homolog 2 (Spns2) acts as a Sphingosine-1-phosphate (S1P) transporter in zebrafish and mice, regulating heart development and lymphocyte trafficking respectively. S1P is a biologically active lysophospholipid with multiple roles in signalling. The mechanism of action of Spns2 is still elusive in mammals. Here, we report that Spns2-deficient mice rapidly lost auditory sensitivity and endocochlear potential (EP) from 2 to 3 weeks old. We found progressive degeneration of sensory hair cells in the organ of Corti, but the earliest defect was a decline in the EP, suggesting that dysfunction of the lateral wall was the primary lesion. In the lateral wall of adult mutants, we observed structural changes of marginal cell boundaries and of strial capillaries, and reduced expression of several key proteins involved in the generation of the EP (Kcnj10, Kcnq1, Gjb2 and Gjb6), but these changes were likely to be secondary. Permeability of the boundaries of the stria vascularis and of the strial capillaries appeared normal. We also found focal retinal degeneration and anomalies of retinal capillaries together with anterior eye defects in Spns2 mutant mice. Targeted inactivation of Spns2 in red blood cells, platelets, or lymphatic or vascular endothelial cells did not affect hearing, but targeted ablation of Spns2 in the cochlea using a Sox10-Cre allele produced a similar auditory phenotype to the original mutation, suggesting that local Spns2 expression is critical for hearing in mammals. These findings indicate that Spns2 is required for normal maintenance of the EP and hence for normal auditory function, and support a role for S1P signalling in hearing.

7 Article Cochlear implantation in the mouse via the round window: effects of array insertion. 2014

Mistry, N / Nolan, L S / Saeed, S R / Forge, A / Taylor, R R. ·UCL Ear Institute, 332 Grays Inn Road, London WC1X 2EE, UK. Electronic address: nina.mistry.11@ucl.ac.uk. · UCL Ear Institute, 332 Grays Inn Road, London WC1X 2EE, UK. Electronic address: l.nolan@ucl.ac.uk. · UCL Ear Institute, 332 Grays Inn Road, London WC1X 2EE, UK. Electronic address: shakeel.saeed@ucl.ac.uk. · UCL Ear Institute, 332 Grays Inn Road, London WC1X 2EE, UK. Electronic address: a.forge@ucl.ac.uk. · UCL Ear Institute, 332 Grays Inn Road, London WC1X 2EE, UK. Electronic address: ruth.r.taylor@ucl.ac.uk. ·Hear Res · Pubmed #24657211.

ABSTRACT: Animal models are the only means of assessing the effects of cochlear implantation (CI) at a cellular and molecular level. The range of naturally occurring and genetically-modified mouse strains which mimic human deafness provide excellent opportunities for auditory research. To date, there are very few studies of CI in mice. The main aims of this study were to develop a reproducible and viable technique to enable long term CI in the mouse and to assess the response of the mouse cochlea to implantation as a means of evaluating the success of the procedure. Electrode array implantation via the round window was performed in C57Bl/6 mice aged 3 and 6 months. The contralateral cochlea acted as a control. Auditory brainstem responses (ABR) were recorded prior to and following CI. Analysis showed greater threshold shifts in the implanted ear compared to the control ear post-implantation, but substantial preservation of hearing. There were no cases in which implantation caused a profound hearing loss across all frequencies. Cone beam computerised tomography and light microscopy confirmed correct placement of the electrode array within the scala tympani. Cochleae were prepared for histological examination. Initial analysis revealed encapsulation of the implant in tissue with morphological characteristics suggestive of fibrosis. Our results show that mouse CI via the round window offers a model for exploring tissue responses to implantation.

8 Article Hearing loss in a mouse model of 22q11.2 Deletion Syndrome. 2013

Fuchs, Jennifer C / Zinnamon, Fhatarah A / Taylor, Ruth R / Ivins, Sarah / Scambler, Peter J / Forge, Andrew / Tucker, Abigail S / Linden, Jennifer F. ·Craniofacial Development & Stem Cell Biology, King's College London, London, United Kingdom. ·PLoS One · Pubmed #24244619.

ABSTRACT: 22q11.2 Deletion Syndrome (22q11DS) arises from an interstitial chromosomal microdeletion encompassing at least 30 genes. This disorder is one of the most significant known cytogenetic risk factors for schizophrenia, and can also cause heart abnormalities, cognitive deficits, hearing difficulties, and a variety of other medical problems. The Df1/+ hemizygous knockout mouse, a model for human 22q11DS, recapitulates many of the deficits observed in the human syndrome including heart defects, impaired memory, and abnormal auditory sensorimotor gating. Here we show that Df1/+ mice, like human 22q11DS patients, have substantial rates of hearing loss arising from chronic middle ear infection. Auditory brainstem response (ABR) measurements revealed significant elevation of click-response thresholds in 48% of Df1/+ mice, often in only one ear. Anatomical and histological analysis of the middle ear demonstrated no gross structural abnormalities, but frequent signs of otitis media (OM, chronic inflammation of the middle ear), including excessive effusion and thickened mucosa. In mice for which both in vivo ABR thresholds and post mortem middle-ear histology were obtained, the severity of signs of OM correlated directly with the level of hearing impairment. These results suggest that abnormal auditory sensorimotor gating previously reported in mouse models of 22q11DS could arise from abnormalities in auditory processing. Furthermore, the findings indicate that Df1/+ mice are an excellent model for increased risk of OM in human 22q11DS patients. Given the frequently monaural nature of OM in Df1/+ mice, these animals could also be a powerful tool for investigating the interplay between genetic and environmental causes of OM.

9 Article Tricellulin deficiency affects tight junction architecture and cochlear hair cells. 2013

Nayak, Gowri / Lee, Sue I / Yousaf, Rizwan / Edelmann, Stephanie E / Trincot, Claire / Van Itallie, Christina M / Sinha, Ghanshyam P / Rafeeq, Maria / Jones, Sherri M / Belyantseva, Inna A / Anderson, James M / Forge, Andrew / Frolenkov, Gregory I / Riazuddin, Saima. ·Laboratory of Molecular Genetics, Division of Pediatric Otolaryngology / Head and Neck Surgery, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio 45229, USA. ·J Clin Invest · Pubmed #23979167.

ABSTRACT: The two compositionally distinct extracellular cochlear fluids, endolymph and perilymph, are separated by tight junctions that outline the scala media and reticular lamina. Mutations in TRIC (also known as MARVELD2), which encodes a tricellular tight junction protein known as tricellulin, lead to nonsyndromic hearing loss (DFNB49). We generated a knockin mouse that carries a mutation orthologous to the TRIC coding mutation linked to DFNB49 hearing loss in humans. Tricellulin was absent from the tricellular junctions in the inner ear epithelia of the mutant animals, which developed rapidly progressing hearing loss accompanied by loss of mechanosensory cochlear hair cells, while the endocochlear potential and paracellular permeability of a biotin-based tracer in the stria vascularis were unaltered. Freeze-fracture electron microscopy revealed disruption of the strands of intramembrane particles connecting bicellular and tricellular junctions in the inner ear epithelia of tricellulin-deficient mice. These ultrastructural changes may selectively affect the paracellular permeability of ions or small molecules, resulting in a toxic microenvironment for cochlear hair cells. Consistent with this hypothesis, hair cell loss was rescued in tricellulin-deficient mice when generation of normal endolymph was inhibited by a concomitant deletion of the transcription factor, Pou3f4. Finally, comprehensive phenotypic screening showed a broader pathological phenotype in the mutant mice, which highlights the non-redundant roles played by tricellulin.

10 Article TRPC3 and TRPC6 are essential for normal mechanotransduction in subsets of sensory neurons and cochlear hair cells. 2012

Quick, Kathryn / Zhao, Jing / Eijkelkamp, Niels / Linley, John E / Rugiero, Francois / Cox, James J / Raouf, Ramin / Gringhuis, Martine / Sexton, Jane E / Abramowitz, Joel / Taylor, Ruth / Forge, Andy / Ashmore, Jonathan / Kirkwood, Nerissa / Kros, Corné J / Richardson, Guy P / Freichel, Marc / Flockerzi, Veit / Birnbaumer, Lutz / Wood, John N. ·Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK. ·Open Biol · Pubmed #22724068.

ABSTRACT: Transient receptor potential (TRP) channels TRPC3 and TRPC6 are expressed in both sensory neurons and cochlear hair cells. Deletion of TRPC3 or TRPC6 in mice caused no behavioural phenotype, although loss of TRPC3 caused a shift of rapidly adapting (RA) mechanosensitive currents to intermediate-adapting currents in dorsal root ganglion sensory neurons. Deletion of both TRPC3 and TRPC6 caused deficits in light touch and silenced half of small-diameter sensory neurons expressing mechanically activated RA currents. Double TRPC3/TRPC6 knock-out mice also showed hearing impairment, vestibular deficits and defective auditory brain stem responses to high-frequency sounds. Basal, but not apical, cochlear outer hair cells lost more than 75 per cent of their responses to mechanical stimulation. FM1-43-sensitive mechanically gated currents were induced when TRPC3 and TRPC6 were co-expressed in sensory neuron cell lines. TRPC3 and TRPC6 are thus required for the normal function of cells involved in touch and hearing, and are potential components of mechanotransducing complexes.

11 Article Alström Syndrome protein ALMS1 localizes to basal bodies of cochlear hair cells and regulates cilium-dependent planar cell polarity. 2011

Jagger, Daniel / Collin, Gayle / Kelly, John / Towers, Emily / Nevill, Graham / Longo-Guess, Chantal / Benson, Jennifer / Halsey, Karin / Dolan, David / Marshall, Jan / Naggert, Jürgen / Forge, Andrew. ·UCL Ear Institute, University College London, 332 Gray’s Inn Road, London WC1X 8EE, UK. d.jagger@ucl.ac.uk ·Hum Mol Genet · Pubmed #21071598.

ABSTRACT: Alström Syndrome is a life-threatening disease characterized primarily by numerous metabolic abnormalities, retinal degeneration, cardiomyopathy, kidney and liver disease, and sensorineural hearing loss. The cellular localization of the affected protein, ALMS1, has suggested roles in ciliary function and/or ciliogenesis. We have investigated the role of ALMS1 in the cochlea and the pathogenesis of hearing loss in Alström Syndrome. In neonatal rat organ of Corti, ALMS1 was localized to the basal bodies of hair cells and supporting cells. ALMS1 was also evident at the basal bodies of differentiating fibrocytes and marginal cells in the lateral wall. Centriolar ALMS1 expression was retained into maturity. In Alms1-disrupted mice, which recapitulate the neurosensory deficits of human Alström Syndrome, cochleae displayed several cyto-architectural defects including abnormalities in the shape and orientation of hair cell stereociliary bundles. Developing hair cells were ciliated, suggesting that ciliogenesis was largely normal. In adult mice, in addition to bundle abnormalities, there was an accelerated loss of outer hair cells and the progressive appearance of large lesions in stria vascularis. Although the mice progressively lost distortion product otoacoustic emissions, suggesting defects in outer hair cell amplification, their endocochlear potentials were normal, indicating the strial atrophy did not affect its function. These results identify previously unrecognized cochlear histopathologies associated with this ciliopathy that (i) implicate ALMS1 in planar cell polarity signaling and (ii) suggest that the loss of outer hair cells causes the majority of the hearing loss in Alström Syndrome.