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1.  Congenital Sensorineural Deafness in Australian Stumpy-Tail Cattle Dogs Is an Autosomal Recessive Trait That Maps to CFA10 
PLoS ONE  2010;5(10):e13364.
Congenital sensorineural deafness is an inherited condition found in many dog breeds, including Australian Stumpy-tail Cattle Dogs (ASCD). This deafness is evident in young pups and may affect one ear (unilateral) or both ears (bilateral). The genetic locus/loci involved is unknown for all dog breeds. The aims of this study were to determine incidence, inheritance mechanism, and possible association of congenital sensorineural deafness with coat colour in ASCD and to identify the genetic locus underpinning this disease.
Methodology/Principal Findings
A total of 315 ASCD were tested for sensorineural deafness using the brain stem auditory evoked response (BAER) test. Disease penetrance was estimated directly, using the ratio of unilaterally to bilaterally deaf dogs, and segregation analysis was performed using Mendel. A complete genome screen was undertaken using 325 microsatellites spread throughout the genome, on a pedigree of 50 BAER tested ASCD in which deafness was segregating. Fifty-six dogs (17.8%) were deaf, with 17 bilaterally and 39 unilaterally deaf. Unilaterally deaf dogs showed no significant left/right bias (p = 0.19) and no significant difference was observed in frequencies between the sexes (p = 0.18). Penetrance of deafness was estimated as 0.72. Testing the association of red/blue coat colour and deafness without accounting for pedigree structure showed that red dogs were 1.8 times more likely to be deaf (p = 0.045). The within family association between red/blue coat colour and deafness was strongly significant (p = 0.00036), with red coat colour segregating more frequently with deafness (COR = 0.48). The relationship between deafness and coat speckling approached significance (p = 0.07), with the lack of statistical significance possibly due to only four families co-segregating for both deafness and speckling. The deafness phenotype was mapped to CFA10 (maximum linkage peak on CFA10 −log10 p-value = 3.64), as was both coat colour and speckling. Fine mapping was then performed on 45 of these 50 dogs and a further 48 dogs (n = 93). Sequencing candidate gene Sox10 in 6 hearing ASCD, 2 unilaterally deaf ASCD and 2 bilaterally deaf ASCD did not reveal any disease-associated mutations.
Deafness in ASCD is an incompletely penetrant autosomal recessive inherited disease that maps to CFA10.
PMCID: PMC2953516  PMID: 20967282
2.  Heritability and complex segregation analysis of deafness in Jack Russell Terriers 
The association between patterns of pigmentation and deafness in the dog has a long-documented history, with reports dating back over one hundred years. Long suspected of having a genetic basis, the search for loci with a pronounced influence in the expression of hearing loss in the dog has yet to be successful. No studies in the dog to date have found a possible influence of a specific colour locus associated with deafness. The present study is intended to evaluate the heritability of deafness in the Jack Russell Terrier (JRT), characterize the mode of inheritance, and evaluate the existence of a sex, coat colour, or coat texture influence on the expression of sensorineural deafness.
The estimation of heritability of deafness in the JRT was 0.22 when deafness was considered a binary (normal/deaf) trait and 0.31 when deafness was considered a three-category (normal/unilateral/bilateral deafness). The influence of coat colour in the incidence of JRT deafness was statistically significant, indicating that dogs with more white are more likely to be deaf. The influence of sex or coat texture was not statistically significant in the incidence of JRT deafness. Complex segregation analysis revealed a model of a single locus with a large effect on the binary measure of hearing loss is not supported.
This is the first attempt, to our knowledge, to characterize a genetic component responsible for deafness in the JRT. The heritability of deafness in the JRT was found to be 0.22 and 0.31 considering deafness to be a two-category or three-category trait, respectively. There appears to be an influence of coat colour on the expression of deafness. In an attempt to characterize the mode of inheritance of deafness in the JRT, a model of a single locus with a large effect on hearing loss is not supported with this data. Further study is needed to determine if a single locus may be influencing deafness in the JRT. While the absence of a clear mode of inheritance complicates genetic dissection of deafness in the JRT, the assembling of this pedigree provides a tool for eventually defining the genetic bases of this disorder.
PMCID: PMC2194672  PMID: 17999773
3.  Variation in Genes Related to Cochlear Biology Is Strongly Associated with Adult-Onset Deafness in Border Collies 
PLoS Genetics  2012;8(9):e1002898.
Domestic dogs can suffer from hearing losses that can have profound impacts on working ability and quality of life. We have identified a type of adult-onset hearing loss in Border Collies that appears to have a genetic cause, with an earlier age of onset (3–5 years) than typically expected for aging dogs (8–10 years). Studying this complex trait within pure breeds of dog may greatly increase our ability to identify genomic regions associated with risk of hearing impairment in dogs and in humans. We performed a genome-wide association study (GWAS) to detect loci underlying adult-onset deafness in a sample of 20 affected and 28 control Border Collies. We identified a region on canine chromosome 6 that demonstrates extended support for association surrounding SNP Chr6.25819273 (p-value = 1.09×10−13). To further localize disease-associated variants, targeted next-generation sequencing (NGS) of one affected and two unaffected dogs was performed. Through additional validation based on targeted genotyping of additional cases (n = 23 total) and controls (n = 101 total) and an independent replication cohort of 16 cases and 265 controls, we identified variants in USP31 that were strongly associated with adult-onset deafness in Border Collies, suggesting the involvement of the NF-κB pathway. We found additional support for involvement of RBBP6, which is critical for cochlear development. These findings highlight the utility of GWAS–guided fine-mapping of genetic loci using targeted NGS to study hereditary disorders of the domestic dog that may be analogous to human disorders.
Author Summary
The domestic dog offers a unique opportunity to study complex disorders similar to those seen in humans, but within the context of the much simpler genetic backgrounds of pure breeds, which represent closed populations. We performed a whole-genome search for genetic risk factors of adult-onset deafness in the Border Collie, a breed of herding dog that relies on acute hearing to perceive and respond to commands while working. Adult-onset deafness in Border Collies typically begins in early adulthood and is similar to age-related hearing loss in humans. This earlier onset has particular impact on the utility of working Border Collies and the livelihoods of their owners, and it appears to have a genetic cause. We identified three genetic variants that were strongly associated with adult-onset deafness in a sample of 405 Border Collies. These variants are located in two genes that have previously been linked to deafness, one involved in ear development and another that appears to mitigate tissue damage in the ear. These results provide new insight regarding genetic risk factors for age-related hearing loss in both dogs and humans.
PMCID: PMC3441646  PMID: 23028339
4.  The Effect of Cochlear-Implant-Mediated Electrical Stimulation on Spiral Ganglion Cells in Congenitally Deaf White Cats 
It has long been observed that loss of auditory receptor cells is associated with the progressive degeneration of spiral ganglion cells. Chronic electrical stimulation via cochlear implantation has been used in an attempt to slow the rate of degeneration in cats neonatally deafened by ototoxic agents but with mixed results. The present study examined this issue using white cats with a history of hereditary deafness as an alternative animal model. Nineteen cats provided new data for this study: four normal-hearing cats, seven congenitally deaf white cats, and eight congenitally deaf white cats with unilateral cochlear implants. Data from additional cats were collected from the literature. Electrical stimulation began at 3 to 4 or 6 to 7 months after birth, and cats received stimulation for approximately 7 h a day, 5 days a week for 12 weeks. Quantitative analysis of spiral ganglion cell counts, cell density, and cell body size showed no marked improvement between cochlear-implanted and congenitally deaf subjects. Average ganglion cell size from cochlear-implanted and congenitally deaf cats was statistically similar and smaller than that of normal-hearing cats. Cell density from cats with cochlear implants tended to decrease within the upper basal and middle cochlear turns in comparison to congenitally deaf cats but remained at congenitally deaf levels within the lower basal and apical cochlear turns. These results provide no evidence that chronic electrical stimulation enhances spiral ganglion cell survival, cell density, or cell size compared to that of unstimulated congenitally deaf cats. Regardless of ganglion neuron status, there is unambiguous restoration of auditory nerve synapses in the cochlear nucleus of these cats implanted at the earlier age.
PMCID: PMC2975880  PMID: 20821032
auditory nerve; cochlea; cochlear nucleus; cochleosaccular degeneration; congenital deafness
5.  The meaning of modern audiological tests in relation to noise-induced deafness: a review 
Wilmot, T. J. (1972).Brit. J. industr. Med.,29, 125-133. The meaning of modern audiological tests in relation to noise-induced deafness: a review. If noise-induced deafness becomes a prescribed disease, it is inevitable that a very large number of workers with hearing difficulties will be discovered and will pose serious problems for both industrial medical officers and otologists working in the National Health Service.
The two main problems are detection of deafness and a decision whether the hearing loss is attributable to noise damage. This paper is concerned largely with the second problem, and outlines in general terms the procedures likely to be required.
After a short discussion of the initial screening procedure the paper concentrates upon those who fail to pass the requisite standard, and describes how modern hearing tests help to differentiate between various types of hearing loss. The traditional belief that conductive deafness and sensorineural deafness are easily differentiated holds true only in classical examples. In practice, in many cases, there are often mixed elements of both. In these individuals the acoustic impedance meter may give important objective evidence on the functions of the Eustachian tube, the tympanic membrane and ossicular chain, and the small but important intratympanic muscles.
Even a pure sensorineural deafness may be present without being caused by noise, and the uses of speech tests and tests for `recruitment' are invaluable in the differential diagnosis of this type of hearing loss.
Whereas noise-induced deafness is usually bilateral, unilateral deafness can be caused or aggravated by noise, and our problems are increased in these cases as efficient `masking' of the good ear is essential before we can obtain any true information about the impaired hearing ear.
One of the other problems is malingering. This may be deliberate, or a person with good hearing may believe it to be impaired; both varieties are now usually known as non-organic hearing loss. Usually the simplest differentiating factor is the ability of someone with non-organic hearing loss to hear the spoken word much more easily than pure tones, and this sign should always make one suspicious of this type of disorder.
Modern auditory analysis should enable the otologist who is equipped with suitable apparatus to diagnose with some precision the site and extent of most auditory disorders and to evaluate the proportion of noise-induced hearing loss in each individual affected.
PMCID: PMC1009389  PMID: 4553812
6.  Unilateral hearing during development: hemispheric specificity in plastic reorganizations 
The present study investigates the hemispheric contributions of neuronal reorganization following early single-sided hearing (unilateral deafness). The experiments were performed on ten cats from our colony of deaf white cats. Two were identified in early hearing screening as unilaterally congenitally deaf. The remaining eight were bilaterally congenitally deaf, unilaterally implanted at different ages with a cochlear implant. Implanted animals were chronically stimulated using a single-channel portable signal processor for two to five months. Microelectrode recordings were performed at the primary auditory cortex under stimulation at the hearing and deaf ear with bilateral cochlear implants. Local field potentials (LFPs) were compared at the cortex ipsilateral and contralateral to the hearing ear. The focus of the study was on the morphology and the onset latency of the LFPs. With respect to morphology of LFPs, pronounced hemisphere-specific effects were observed. Morphology of amplitude-normalized LFPs for stimulation of the deaf and the hearing ear was similar for responses recorded at the same hemisphere. However, when comparisons were performed between the hemispheres, the morphology was more dissimilar even though the same ear was stimulated. This demonstrates hemispheric specificity of some cortical adaptations irrespective of the ear stimulated. The results suggest a specific adaptation process at the hemisphere ipsilateral to the hearing ear, involving specific (down-regulated inhibitory) mechanisms not found in the contralateral hemisphere. Finally, onset latencies revealed that the sensitive period for the cortex ipsilateral to the hearing ear is shorter than that for the contralateral cortex. Unilateral hearing experience leads to a functionally-asymmetric brain with different neuronal reorganizations and different sensitive periods involved.
PMCID: PMC3841817  PMID: 24348345
cochlear implant; plasticity; single-sided deafness; critical periods; development
7.  Neural networks mediating sentence reading in the deaf 
The present work addresses the neural bases of sentence reading in deaf populations. To better understand the relative role of deafness and spoken language knowledge in shaping the neural networks that mediate sentence reading, three populations with different degrees of English knowledge and depth of hearing loss were included—deaf signers, oral deaf and hearing individuals. The three groups were matched for reading comprehension and scanned while reading sentences. A similar neural network of left perisylvian areas was observed, supporting the view of a shared network of areas for reading despite differences in hearing and English knowledge. However, differences were observed, in particular in the auditory cortex, with deaf signers and oral deaf showing greatest bilateral superior temporal gyrus (STG) recruitment as compared to hearing individuals. Importantly, within deaf individuals, the same STG area in the left hemisphere showed greater recruitment as hearing loss increased. To further understand the functional role of such auditory cortex re-organization after deafness, connectivity analyses were performed from the STG regions identified above. Connectivity from the left STG toward areas typically associated with semantic processing (BA45 and thalami) was greater in deaf signers and in oral deaf as compared to hearing. In contrast, connectivity from left STG toward areas identified with speech-based processing was greater in hearing and in oral deaf as compared to deaf signers. These results support the growing literature indicating recruitment of auditory areas after congenital deafness for visually-mediated language functions, and establish that both auditory deprivation and language experience shape its functional reorganization. Implications for differential reliance on semantic vs. phonological pathways during reading in the three groups is discussed.
PMCID: PMC4050738  PMID: 24959127
reading; deaf; native signers; oral training; sentence comprehension; Superior Temporal Gyrus
8.  Mutations in MITF and PAX3 Cause “Splashed White” and Other White Spotting Phenotypes in Horses 
PLoS Genetics  2012;8(4):e1002653.
During fetal development neural-crest-derived melanoblasts migrate across the entire body surface and differentiate into melanocytes, the pigment-producing cells. Alterations in this precisely regulated process can lead to white spotting patterns. White spotting patterns in horses are a complex trait with a large phenotypic variance ranging from minimal white markings up to completely white horses. The “splashed white” pattern is primarily characterized by an extremely large blaze, often accompanied by extended white markings at the distal limbs and blue eyes. Some, but not all, splashed white horses are deaf. We analyzed a Quarter Horse family segregating for the splashed white coat color. Genome-wide linkage analysis in 31 horses gave a positive LOD score of 1.6 in a region on chromosome 6 containing the PAX3 gene. However, the linkage data were not in agreement with a monogenic inheritance of a single fully penetrant mutation. We sequenced the PAX3 gene and identified a missense mutation in some, but not all, splashed white Quarter Horses. Genome-wide association analysis indicated a potential second signal near MITF. We therefore sequenced the MITF gene and found a 10 bp insertion in the melanocyte-specific promoter. The MITF promoter variant was present in some splashed white Quarter Horses from the studied family, but also in splashed white horses from other horse breeds. Finally, we identified two additional non-synonymous mutations in the MITF gene in unrelated horses with white spotting phenotypes. Thus, several independent mutations in MITF and PAX3 together with known variants in the EDNRB and KIT genes explain a large proportion of horses with the more extreme white spotting phenotypes.
Author Summary
White spotting coat color phenotypes are the result of aberrations in the development of melanocytes. The analysis of domestic animals with heritable white spotting phenotypes thus helps to better understand the complicated genetic network controlling the proliferation, migration, differentiation, and survival of pigment producing cells. We analyzed the so-called splashed white phenotype in horses, which is characterized by a very distinctive large blaze, extended white markings on the legs, and blue eyes. Splashed white horses are also frequently deaf. However, the phenotype is quite variable and, in some horses with minimal expression, the splashed white phenotype cannot be unambiguously discriminated from the “common” white markings. We studied horses from various breeds and found one mutation in the PAX3 gene and two mutations in the MITF gene that cause the splashed white phenotype. A third mutation in the MITF gene, which we found in a single Franches-Montagnes horse, causes a new coat color phenotype, termed macchiato. Similar mutations in humans cause either Waardenburg or Tietz syndrome, which both are characterized by pigmentation defects and a predisposition for deafness. Our study reveals the molecular basis for a significant proportion of white spotting phenotypes that are intermediate between completely unpigmented horses and common white markings.
PMCID: PMC3325211  PMID: 22511888
9.  Characterisation and genetic mapping of a new X linked deafness syndrome 
Journal of Medical Genetics  2000;37(11):836-841.
BACKGROUND—Hereditary forms of hearing loss are classified as syndromic, when deafness is associated with other clinical features, or non-syndromic, when deafness occurs without other clinical features. Many types of syndromic deafness have been described, some of which have been mapped to specific chromosomal regions.
METHODS—Here we describe a family with progressive sensorineural hearing loss, cognitive impairment, facial dysmorphism, and variable other features, transmitted by apparent X linked recessive inheritance. Haplotype analysis of PCR products spanning the X chromosome and direct sequencing of candidate genes were used to begin characterising the molecular basis of features transmitted in this family. Comparison to known syndromes involving deafness, mental retardation, facial dysmorphism, and other clinical features was performed by review of published reports and personal discussions.
RESULTS—Genetic mapping places the candidate locus for this syndrome within a 48 cM region on Xq1-21. Candidate genes including COL4A5, DIAPH, and POU3F4 were excluded by clinical and molecular analyses.
CONCLUSIONS—The constellation of clinical findings in this family (deafness, cognitive impairment, facial dysmorphism, variable renal and genitourinary abnormalities, and late onset pancytopenia), along with a shared haplotype on Xq1-21, suggests that this represents a new form of syndromic deafness. We discuss our findings in comparison to several other syndromic and non-syndromic deafness loci that have been mapped to the X chromosome.

Keywords: deafness; mental retardation; X chromosome; learning disorder
PMCID: PMC1734461  PMID: 11073537
10.  The effect of long-term unilateral deafness on the activation pattern in the auditory cortices of French-native speakers: influence of deafness side 
BMC Neuroscience  2009;10:23.
In normal-hearing subjects, monaural stimulation produces a normal pattern of asynchrony and asymmetry over the auditory cortices in favour of the contralateral temporal lobe. While late onset unilateral deafness has been reported to change this pattern, the exact influence of the side of deafness on central auditory plasticity still remains unclear. The present study aimed at assessing whether left-sided and right-sided deafness had differential effects on the characteristics of neurophysiological responses over auditory areas. Eighteen unilaterally deaf and 16 normal hearing right-handed subjects participated. All unilaterally deaf subjects had post-lingual deafness. Long latency auditory evoked potentials (late-AEPs) were elicited by two types of stimuli, non-speech (1 kHz tone-burst) and speech-sounds (voiceless syllable/pa/) delivered to the intact ear at 50 dB SL. The latencies and amplitudes of the early exogenous components (N100 and P150) were measured using temporal scalp electrodes.
Subjects with left-sided deafness showed major neurophysiological changes, in the form of a more symmetrical activation pattern over auditory areas in response to non-speech sound and even a significant reversal of the activation pattern in favour of the cortex ipsilateral to the stimulation in response to speech sound. This was observed not only for AEP amplitudes but also for AEP time course. In contrast, no significant changes were reported for late-AEP responses in subjects with right-sided deafness.
The results show that cortical reorganization induced by unilateral deafness mainly occurs in subjects with left-sided deafness. This suggests that anatomical and functional plastic changes are more likely to occur in the right than in the left auditory cortex. The possible perceptual correlates of such neurophysiological changes are discussed.
PMCID: PMC2662863  PMID: 19309511
11.  A new X linked recessive deafness syndrome with blindness, dystonia, fractures, and mental deficiency is linked to Xq22. 
Journal of Medical Genetics  1995;32(4):257-263.
X linked recessive deafness accounts for only 1.7% of all childhood deafness. Only a few of the at least 28 different X linked syndromes associated with hearing impairment have been characterised at the molecular level. In 1960, a large Norwegian family was reported with early onset progressive sensorineural deafness, which was indexed in McKusick as DFN-1, McKusick 304700. No associated symptoms were described at that time. This family has been restudied clinically. Extensive neurological, neurophysiological, neuroradiological, and biochemical, as well as molecular techniques, have been applied to characterise the X linked recessive syndrome. The family history and extensive characterisation of 16 affected males in five generations confirmed the X linked recessive inheritance and the postlingual progressive nature of the sensorineural deafness. Some obligate carrier females showed signs of minor neuropathy and mild hearing impairment. Restudy of the original DFN-1 family showed that the deafness is part of a progressive X linked recessive syndrome, which includes visual disability leading to cortical blindness, dystonia, fractures, and mental deficiency. Linkage analysis indicated that the gene was linked to locus DXS101 in Xq22 with a lod score of 5.37 (zero recombination). Based on lod-1 support interval of the multipoint analysis, the gene is located in a region spanning from 5 cM proximal to 3 cM distal to this locus. As the proteolipid protein gene (PLP) is within this region and mutations have been shown to be associated with non-classical PMD (Pelizaeus-Merzbacher disease), such as complex X linked hereditary spastic paraplegia, PLP may represent a candidate gene for this disorder. This family represents a new syndrome (Mohr-Tranebjaerg syndrome, MTS) and provides significant new information about a new X linked recessive sydromic type of deafness which was previously thought to be isolated deafness.
PMCID: PMC1050371  PMID: 7643352
12.  Systematic review of the literature on the clinical effectiveness of the cochlear implant procedure in paediatric patients 
The aim of this systematic review of the literature was to summarize the results of scientific publications on the clinical effectiveness of the cochlear implant (CI) procedure in children. The members of the Working Group first examined existing national and international literature and the principal international guidelines on the procedure. They considered as universally-accepted the usefulness/effectiveness of unilateral cochlear implantation in severely-profoundly deaf children. Accordingly, they focused attention on systematic reviews addressing clinical effectiveness and cost/efficacy of the CI procedure, with particular regard to the most controversial issues for which international consensus is lacking. The following aspects were evaluated: post-CI outcomes linked to precocity of CI; bilateral (simultaneous/ sequential) CI vs. unilateral CI and vs. bimodal stimulation; benefits derived from CI in deaf children with associated disabilities. With regard to the outcomes after implantation linked to precocity of intervention, there are few studies comparing post-CI outcomes in children implanted within the first year of life with those of children implanted in the second year. The selected studies suggest that children implanted within the first year of life present hearing and communicative outcomes that are better than those of children implanted after 12 months of age. Concerning children implanted after the first year of life, all studies confirm an advantage with respect to implant precocity, and many document an advantage in children who received cochlear implants under 18 months of age compared to those implanted at a later stage. With regard to bilateral CI, the studies demonstrate that compared to unilateral CI, bilateral CI offers advantages in terms of hearing in noise, sound localization and during hearing in a silent environment. There is, however, a wide range of variability. The studies also document the advantages after sequential bilateral CI. In these cases, a short interval between interventions, precocity of the first CI and precocity of the second CI are considered positive prognostic factors. In deaf children with associated disabilities, the studies analyzed evidence that the CI procedure is also suitable for children with disabilities associated with deafness, and that even these children may benefit from the procedure, even if these may be slower and inferior to those in children with isolated deafness, especially in terms of high communicative and perceptive skills.
PMCID: PMC3262414  PMID: 22287820
Cochlear implant; Bilateral cochlear implant; Severe to profound hearing loss; Disabilities
13.  Multisensory Training Improves Auditory Spatial Processing following Bilateral Cochlear Implantation 
The Journal of Neuroscience  2014;34(33):11119-11130.
Cochlear implants (CIs) partially restore hearing to the deaf by directly stimulating the inner ear. In individuals fitted with CIs, lack of auditory experience due to loss of hearing before language acquisition can adversely impact outcomes. For example, adults with early-onset hearing loss generally do not integrate inputs from both ears effectively when fitted with bilateral CIs (BiCIs). Here, we used an animal model to investigate the effects of long-term deafness on auditory localization with BiCIs and approaches for promoting the use of binaural spatial cues. Ferrets were deafened either at the age of hearing onset or as adults. All animals were implanted in adulthood, either unilaterally or bilaterally, and were subsequently assessed for their ability to localize sound in the horizontal plane. The unilaterally implanted animals were unable to perform this task, regardless of the duration of deafness. Among animals with BiCIs, early-onset hearing loss was associated with poor auditory localization performance, compared with late-onset hearing loss. However, performance in the early-deafened group with BiCIs improved significantly after multisensory training with interleaved auditory and visual stimuli. We demonstrate a possible neural substrate for this by showing a training-induced improvement in the responsiveness of auditory cortical neurons and in their sensitivity to interaural level differences, the principal localization cue available to BiCI users. Importantly, our behavioral and physiological evidence demonstrates a facilitative role for vision in restoring auditory spatial processing following potential cross-modal reorganization. These findings support investigation of a similar training paradigm in human CI users.
PMCID: PMC4131019  PMID: 25122908
auditory cortex; cochlear implant; cross-modal plasticity; hearing loss; multisensory; sound localization
14.  Somatosensory and Visual Crossmodal Plasticity in the Anterior Auditory Field of Early-Deaf Cats 
Hearing research  2011;280(1-2):38-47.
It is well known that the postnatal loss of sensory input in one modality can result in crossmodal reorganization of the deprived cortical areas, but deafness fails to induce crossmodal effects in cat primary auditory cortex (A1). Because the core auditory regions (A1, and anterior auditory field AAF) are arranged as separate, parallel processors, it cannot be assumed that early-deafness affects one in the same manner as the other. The present experiments were conducted to determine if crossmodal effects occur in the anterior auditory field (AAF). Using mature cats (n=3), ototoxically deafened postnatally, single-unit recordings were made in the gyral and sulcal portions of the AAF. In contrast to the auditory responsivity found in the hearing controls, none of the neurons in early-deafened AAF were activated by auditory stimulation. Instead, the majority (78%) were activated by somatosensory cues, while fewer were driven by visual stimulation (44%; values include unisensory and bimodal neurons). Somatosensory responses could be activated from all locations on the body surface but most often occurred on the head, were often bilateral (e.g., occupied portions of both sides of the body), and were primarily excited by low-threshold hair receptors. Visual receptive fields were large, collectively represented the contralateral visual field, and exhibited conventional response properties such as movement direction and velocity preferences. These results indicate that, following postnatal deafness, both somatosensory and visual modalities participate in crossmodal re-innervation of the AAF, consistent with the growing literature that documents deafness-induced crossmodal plasticity outside A1.
PMCID: PMC3134631  PMID: 21354286
15.  A Novel Decorin Gene Mutation in Congenital Hereditary Stromal Dystrophy: A Korean Family 
A 43-year-old man developed decreased vision in the right eye that had persisted for seven years. Under slit lamp examination, corneal clouding was noted with normal endothelium and ocular structure. From the clinical evidence, we suspected that the patient had congenital hereditary stromal dystrophy (CHSD). He and his family underwent a genetic analysis. Penetrating keratoplasty was conducted, and the corneal button was investigated for histopathologic confirmation via both light and electron microscopy. The histopathologic results revealed mildly loosened stromal structures, which exhibited an almost normal arrangement and differed slightly from the previous findings of CHSD cases. With regard to the genetic aspects, the patient and his mother harbored a novel point mutation of the decorin gene. This genetic mutation is also distinct from previously described deletion mutations of the decorin gene. This case involved delayed penetration of mild clinical symptoms with the histological feature of a loosened fiber arrangement in the corneal stroma. We concluded that this condition was a mild form of CHSD. However, from another perspective, this case could be considered as "decorin gene-associated corneal dystrophy," which is distinct from CHSD. Further evaluation will be required for appropriate clinical, histopathologic and genetic approaches for such cases.
PMCID: PMC3408537  PMID: 22870031
Decorin; Hereditary corneal dystrophy; Point mutation
16.  Bilateral Effects of Unilateral Cochlear Implantation in Congenitally Deaf Cats 
The Journal of comparative neurology  2010;518(12):2382-2404.
Congenital deafness results in synaptic abnormalities in auditory nerve endings. These abnormalities are most prominent in terminals called endbulbs of Held, which are large, axosomatic synaptic endings whose size and evolutionary conservation emphasize their importance. Transmission jitter, delay, or failures, which would corrupt the processing of timing information, are possible consequences of the perturbations at this synaptic junction. We sought to determine whether electrical stimulation of the congenitally deaf auditory system via cochlear implants would restore the endbulb synapses to their normal morphology. Three and 6-month-old congenitally deaf cats received unilateral cochlear implants and were stimulated for a period of 10–19 weeks by using human speech processors. Implanted cats exhibited acoustic startle responses and were trained to approach their food dish in response to a specific acoustic stimulus. Endbulb synapses were examined by using serial section electron microscopy from cohorts of cats with normal hearing, congenital deafness, or congenital deafness with a cochlear implant. Synapse restoration was evident in endbulb synapses on the stimulated side of cats implanted at 3 months of age but not at 6 months. In the young implanted cats, post-synaptic densities exhibited normal size, shape, and distribution, and synaptic vesicles had density values typical of hearing cats. Synapses of the contralateral auditory nerve in early implanted cats also exhibited synapses with more normal structural features. These results demonstrate that electrical stimulation with a cochlear implant can help preserve central auditory synapses through direct and indirect pathways in an age-dependent fashion.
PMCID: PMC3936022  PMID: 20437534
auditory; auditory nerve; cochlear nucleus; deafness; synapse; ultrastructure
17.  Role of auditory brain function assessment by spect in cochlear implant side selection 
Pre-surgery evaluation, indications for cochlear implantation and expectations in terms of post-operative functional results remain challenging topics in pre-lingually deaf adults. Our study has the purpose of determining the benefits of Single Photon Emission Tomography (SPECT) assessment in pre-surgical evaluation of pre-lingually deaf adults who are candidates for cochlear implantation. In 7 pre-lingually profoundly deaf patients, brain SPECT was performed at baseline conditions and in bilateral simultaneous multi-frequency acoustic stimulation. Six sagittal tomograms of both temporal cortices were used for semi-quantitative analysis in each patient. Percentage increases in cortical perfusion resulting from auditory stimulation were calculated. The results showed an inter-hemispherical asymmetry of the activation extension and intensity in the stimulated temporal areas. Consistent with the obtained brain activation data, patients were implanted preferring the side that showed higher activation after acoustic stimulus. Considering the increment in auditory perception performances, it was possible to point out a relationship between cortical brain activity shown by SPECT and hearing performances, and, even more significant, a correlation between post-operative functional performances and the activation of the most medial part of the sagittal temporal tomograms, corresponding to medium-high frequencies. In light of these findings, we believe that brain SPECT could be considered in the evaluation of deaf patients candidate for cochlear implantation, and that it plays a major role in functional assessment of the auditory cortex of pre-lingually deaf subjects, even if further studies are necessary to conclusively establish its utility. Further developments of this technique are possible by using trans-tympanic electrical stimulation of the cochlear promontory, which could give the opportunity to study completely deaf patients, whose evaluation is objectively difficult with current audiological methods.
PMCID: PMC3631813  PMID: 23620636
Brain SPECT; Cochlear implant; Auditory cortex activation; Pre-lingually deaf
18.  Congenital and Prolonged Adult-Onset Deafness Cause Distinct Degradations in Neural ITD Coding with Bilateral Cochlear Implants 
Bilateral cochlear implant (CI) users perform poorly on tasks involving interaural time differences (ITD), which are critical for sound localization and speech reception in noise by normal-hearing listeners. ITD perception with bilateral CI is influenced by age at onset of deafness and duration of deafness. We previously showed that ITD coding in the auditory midbrain is degraded in congenitally deaf white cats (DWC) compared to acutely deafened cats (ADC) with normal auditory development (Hancock et al., J. Neurosci, 30:14068). To determine the relative importance of early onset of deafness and prolonged duration of deafness for abnormal ITD coding in DWC, we recorded from single units in the inferior colliculus of cats deafened as adults 6 months prior to experimentation (long-term deafened cats, LTDC) and compared neural ITD coding between the three deafness models. The incidence of ITD-sensitive neurons was similar in both groups with normal auditory development (LTDC and ADC), but significantly diminished in DWC. In contrast, both groups that experienced prolonged deafness (LTDC and DWC) had broad distributions of best ITDs around the midline, unlike the more focused distributions biased toward contralateral-leading ITDs present in both ADC and normal-hearing animals. The lack of contralateral bias in LTDC and DWC results in reduced sensitivity to changes in ITD within the natural range. The finding that early onset of deafness more severely degrades neural ITD coding than prolonged duration of deafness argues for the importance of fitting deaf children with sound processors that provide reliable ITD cues at an early age.
PMCID: PMC3642270  PMID: 23462803
binaural hearing; congenital deafness; inferior colliculus; cochlear implants; ITD
19.  Prevalence and Potential Genetic Determinants of Sensorineural Deafness in KCNQ1 Homozygosity and Compound Heterozygosity 
Homozygous or compound heterozygous mutations in KCNQ1 cause Jervell and Lange-Nielsen syndrome (JLNS), a rare, autosomal recessive form of long QT syndrome (LQTS) characterized by deafness, marked QT prolongation, and a high risk of sudden death. However, it is not understood why some individuals with mutations on both KCNQ1 alleles present without deafness. Here, we sought to determine the prevalence and genetic determinants of this phenomenon in a large referral population of LQTS patients.
Methods and Results
Retrospective analysis of all LQTS patients evaluated from July 1998 to April 2012 was used to identify those with ≥1 KCNQ1 mutation. Of the 249 KCNQ1-positive patients identified, 15 patients (6.0%) harbored a rare putative pathogenic mutation on both KCNQ1 alleles. Surprisingly, 11 (73%) of these patients presented without the sensorineural deafness associated with JLNS. The degree of QT interval prolongation and number of breakthrough cardiac events were similar between cases with and without deafness. Interestingly, truncating mutations were more prevalent in JLNS (79%) than non-deaf cases (36%, p<0.001) derived from this study and those in the literature.
Here, we provide evidence that the “recessive” inheritance of a severe LQT1 phenotype in the absence of an auditory phenotype may represent a more common pattern of LQTS inheritance than previously anticipated and that these cases should be treated as a higher-risk LQTS subset similar to their JLNS counterparts. Furthermore, mutation type may serve as a genetic determinant of deafness, but not cardiac expressivity, in individuals harboring ≥1 KCNQ1 mutation on each allele.
PMCID: PMC3683572  PMID: 23392653
long QT syndrome; genetics; ion channels; pediatrics; sudden cardiac death
20.  Mitigation of informational masking in individuals with single-sided deafness by integrated bone conduction hearing aids 
Ear and hearing  2014;35(1):10.1097/AUD.0b013e31829d14e8.
To confirm an increased susceptibility to informational masking among individuals with single-sided deafness (SSD). To demonstrate a reduction in informational masking when SSD is treated with an integrated bone conduction hearing aid (IBC). To identify the acoustic cues that contribute to IBC-aided masking release. To determine the effects of device experience on the IBC advantage.
Informational masking was evaluated with the coordinate-response measure. Participants performed the task by reporting color and number coordinates that changed randomly within target sentences. The target sentences were presented in free field accompanied by 0 – 3 distracting sentences. Target and distracting sentences were spoken by different talkers and originated from different source locations, creating two sources of information for auditory streaming. Susceptibility to informational masking was inferred from the error rates of unaided SSD patients relative to normal controls. These baseline measures were derived by testing inexperienced IBC users without the device on the day of their initial fitting. The benefits of IBC-aided listening were assessed by measuring the aided performance of users who had at least three months device experience. The acoustic basis of the listening advantage was isolated by correlating response errors with the voice pitch and location of distracting sentences. The effects of learning on cue effectiveness were evaluated by comparing the error rates of experienced and inexperienced users.
Unaided SSD participants (inexperienced users) performed as well as normal controls when tested without distracting sentences but produced significantly higher error rates when tested with distracting sentences. Most errors involved responding with coordinates that were contained in distracting sentences. This increased susceptibility to informational masking was significantly reduced when experienced IBC users were tested with the device. The listening advantage was most strongly correlated with the availability of voice pitch cues, although performance was also influenced by the location of distracting sentences. Directional asymmetries appear to be dictated by location-dependent cues that are derived from the distinctive transmission characteristics of IBC stimulation. Experienced users made better use of these cues than inexperienced users.
These results suggest that informational masking is a significant source of communication impairment among individuals with SSD. Despite the lateralization of auditory function, unaided SSD subjects experience informational masking when distractors occur in either the deaf or normal spatial hemifield. Restoration of aural sensitivity in the deaf hemifield with an IBC enhances speech intelligibility under complex listening conditions, presumably by providing additional sound segregation cues that are derived from voice pitch and spatial location. The optimal utilization of these cues is not immediate, but a significant listening advantage is observed after three months of unstructured use.
PMCID: PMC3872507  PMID: 24067501
21.  Clinical profile of hearing loss in children with congenital cytomegalovirus (CMV) infection: CMV DNA diagnosis using preserved umbilical cord 
Acta Oto-Laryngologica  2011;131(9):976-982.
Congenital cytomegalovirus (CMV) infection is a major cause of bilateral and unilateral sensorineural hearing loss (SNHL) in children, accounting for 9.0% of SNHL cases. The diagnostic rate using combined genetic deafness test and CMV DNA detection test was determined to be 46.4% in bilateral profound SNHL.
The present study investigated the prevalence of congenital CMV infection diagnosed retrospectively by detection of CMV DNA in dried umbilical cord specimens from children with unilateral or bilateral SNHL up to the age of 12 years.
Preserved dried umbilical cords were collected from 134 children with bilateral (46 children) or unilateral (88 children) SNHL. DNA was extracted from the dried umbilical cords and CMV DNA was detected by quantitative PCR. Genetic deafness tests based on the invader assay were performed in children with bilateral SNHL.
CMV DNA from the dried umbilical cords was detected in 8.7% of the bilateral SNHL and 9.1% of unilateral SNHL. Deafness gene mutations were identified in 21.7% (10/46) of children with bilateral SNHL.
PMCID: PMC3490478  PMID: 21612560
Sensorineural hearing loss; GJB2; SLC26A4
22.  SLC3A1 and SLC7A9 Mutations in Autosomal Recessive or Dominant Canine Cystinuria: A New Classification System 
Cystinuria, one of the first recognized inborn errors of metabolism, has been reported in many dog breeds.
To determine urinary cystine concentrations, inheritance and mutations in the SLC3A1 and SLC7A9 genes associated with cystinuria in 3 breeds.
Mixed and purebred Labrador Retrievers (n=6), Australian Cattle Dogs (6), Miniature Pinschers (4) and 1 mixed breed dog with cystine urolithiasis, relatives and control dogs.
Urinary cystinuria and aminoaciduria was assessed and exons of the SLC3A1 and SLC7A9 genes were sequenced from genomic DNA.
In each breed, male and female dogs, independent of neuter status, were found to form calculi. A frameshift mutation in SLC3A1 (c.350delG) resulting in a premature stop codon was identified in autosomal-recessive (AR) cystinuria in Labrador Retrievers and mixed breed dogs. A 6 bp deletion (c.1095_1100del) removing 2 threonines in SLC3A1 was found in autosomal-dominant (AD) cystinuria with a more severe phenotype in homozygous than in heterozygous Australian Cattle Dogs. A missense mutation in SLC7A9 (c.964G>A) was discovered in AD cystinuria in Miniature Pinschers with only heterozygous affected dogs observed to date. Breed specific DNA tests were developed, but the prevalence of each mutation remains unknown.
Conclusions and clinical importance
These studies describe the first AD inheritance and the first putative SLC7A9 mutation to cause cystinuria in dogs and expand our understanding of this phenotypically and genetically heterogeneous disease, leading to a new classification system for canine cystinuria and better therapeutic management and genetic control in these breeds.
PMCID: PMC3946761  PMID: 24001348
Metabolic disease; urolithiasis; nephropathy; hereditary disease
23.  A Claudin-9–Based Ion Permeability Barrier Is Essential for Hearing 
PLoS Genetics  2009;5(8):e1000610.
Hereditary hearing loss is one of the most common birth defects, yet the majority of genes required for audition is thought to remain unidentified. Ethylnitrosourea (ENU)–mutagenesis has been a valuable approach for generating new animal models of deafness and discovering previously unrecognized gene functions. Here we report on the characterization of a new ENU–induced mouse mutant (nmf329) that exhibits recessively inherited deafness. We found a widespread loss of sensory hair cells in the hearing organs of nmf329 mice after the second week of life. Positional cloning revealed that the nmf329 strain carries a missense mutation in the claudin-9 gene, which encodes a tight junction protein with unknown biological function. In an epithelial cell line, heterologous expression of wild-type claudin-9 reduced the paracellular permeability to Na+ and K+, and the nmf329 mutation eliminated this ion barrier function without affecting the plasma membrane localization of claudin-9. In the nmf329 mouse line, the perilymphatic K+ concentration was found to be elevated, suggesting that the cochlear tight junctions were dysfunctional. Furthermore, the hair-cell loss in the claudin-9–defective cochlea was rescued in vitro when the explanted hearing organs were cultured in a low-K+ milieu and in vivo when the endocochlear K+-driving force was diminished by deletion of the pou3f4 gene. Overall, our data indicate that claudin-9 is required for the preservation of sensory cells in the hearing organ because claudin-9–defective tight junctions fail to shield the basolateral side of hair cells from the K+-rich endolymph. In the tight-junction complexes of hair cells, claudin-9 is localized specifically to a subdomain that is underneath more apical tight-junction strands formed by other claudins. Thus, the analysis of claudin-9 mutant mice suggests that even the deeper (subapical) tight-junction strands have biologically important ion barrier function.
Author Summary
Hereditary deafness is a common birth defect in the human population, yet the majority of genes required for audition is thought to be unidentified. Genetic approaches in the mouse have greatly contributed to our understanding of the molecular mechanisms that underlie hearing. Random mutagenesis of mice, identification of deaf mutants, and subsequent analysis of the deafness-causing gene defects has led to the discovery of several previously unrecognized gene functions. Here, we report on the characterization of a new mutant mouse line (nmf329) that exhibits profound hearing loss and loss of sensory cells in the auditory organ. Genetic analysis reveals that these animals carry a mutation in the claudin-9 gene, which encodes a protein with hitherto unknown biological function. We have found that normal claudin-9—but not a mutant form—inhibits the paracellular movement of certain ions. The lack of the claudin-9 ion barrier in the inner ear leads to changes in ionic conditions that can account for the loss of sensory cells in the mutant mice. Within the cell–cell junctions, the claudin-9 layer is located basal to those of other claudins. Thus, our analysis of claudin-9–deficient animals suggests that even the deeper layers of claudins have important ion barrier function.
PMCID: PMC2720454  PMID: 19696885
24.  Suicide in deaf populations: a literature review 
Studies have found that deaf individuals have higher rates of psychiatric disorder than those who are hearing, while at the same time encountering difficulties in accessing mental health services. These factors might increase the risk of suicide. However, the burden of suicidal behaviour in deaf people is currently unknown.
The aim of the present review was to provide a summary of literature on suicidal behaviour with specific reference to deaf individuals. The objectives of the review were to establish the incidence and prevalence of suicidal behaviour in deaf populations; describe risk factors for suicidal behaviour in deaf populations; describe approaches to intervention and suicide prevention that have been used in deaf populations.
A number of electronic databases (e.g. Medline, PsycINFO, CINAHL, EMBASE, Dissertation Abstracts International, Web of Science, ComDisDome, ASSIA, Education Sage Full Text, Google Scholar, and the grey literature databases FADE and SIGLE) were explored using a combination of key words and medical subject headings as search terms. Reference lists of papers were also searched. The Science and Social Sciences Citation Index electronic databases were used to identify studies that had cited key papers. We also contacted experts and organisations with an interest in the field.
Very few studies focussed specifically on suicide in deaf populations. Those studies that were included (n = 13) generally involved small and unrepresentative samples. There were limited data on the rate of suicidal behaviour in deaf people. One study reported evidence of hearing impairment in 0.2% of all suicide deaths. Another found that individuals with tinnitus seen in specialist clinics had an elevated rate of suicide compared to the general population. The rates of attempted suicide in deaf school and college students during the previous year ranged from 1.7% to 18%, with lifetime rates as high as 30%. Little evidence was found to suggest that risk factors for suicide in deaf people differed systematically from those in the general population. However, studies did report higher levels of depression and higher levels of perceived risk among deaf individuals than hearing control groups. No firm evidence was found regarding the effectiveness of suicide prevention strategies in deaf people, but suggested strategies include developing specific screening tools, training clinical staff, promoting deaf awareness, increasing the availability of specialist mental health services for deaf people.
There is a significant gap in our understanding of suicide in deaf populations. Clinicians should be aware of the possible association between suicide and deafness. Specialist mental health services should be readily accessible to deaf individuals and specific preventative strategies may be of benefit. However, further research using a variety of study designs is needed to increase our understanding of this issue.
PMCID: PMC2093933  PMID: 17922904
25.  Curing tinnitus with a Cochlear Implant in a patient with unilateral sudden deafness: a case report 
Cases Journal  2009;2:7462.
Cochlear implantation is a routine procedure for patients with bilateral profound sensorineural hearing loss. Some reports demonstrated a suppression of tinnitus as a side-effect after implantation. We describe the case of a 55-year-old man suffering from severe right-sided tinnitus in consequence of sudden right-sided deafness. Multiple therapeutic efforts including intravenous steroids and tympanoscopy with grafting of the round window remained unsuccessful. One year after onset of symptoms right-sided cochlear implantation was performed, which resulted in a complete abolishment of tinnitus after activating the implant. Severe unilateral tinnitus after sudden deafness might represent a new indication for cochlear implantation.
PMCID: PMC2740131  PMID: 19829970

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