Major Contribution of GREB1L Alterations to Severe Inner Ear Malformation Largely in a Non-mendelian Fashion.
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SUBMITTER: Kim BJ
PROVIDER: S-EPMC8901951 | biostudies-literature | 2022 Feb
REPOSITORIES: biostudies-literature
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Major Contribution of GREB1L Alterations to Severe Inner Ear Malformation Largely in a Non-mendelian Fashion.
Kim Bong Jik BJ Jeon Hyoungwon H Lee Sang-Yeon SY Yi Nayoung N Han Jin Hee JH Seo Go Hun GH Oh Seung-Ha SH Choi Byung Yoon BY
Clinical and experimental otorhinolaryngology 20220112 1
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Project description:Congenital inner ear malformations affecting both the osseous and membranous labyrinth can have a devastating impact on hearing and language development. With the exception of an enlarged vestibular aqueduct, non-syndromic inner ear malformations are rare, and their underlying molecular biology has thus far remained understudied. To identify molecular factors that might be important in the developing inner ear, we adopted a family-based trio exome sequencing approach in young unrelated subjects with severe inner ear malformations. We identified two previously unreported de novo loss-of-function variants in GREB1L [c.4368G>T;p.(Glu1410fs) and c.982C>T;p.(Arg328*)] in two affected subjects with absent cochleae and eighth cranial nerve malformations. The cochlear aplasia in these affected subjects suggests that a developmental arrest or problem at a very early stage of inner ear development exists, e.g., during the otic pit formation. Craniofacial Greb1l RNA expression peaks in mice during this time frame (E8.5). It also peaks in the developing inner ear during E13-E16, after which it decreases in adulthood. The crucial function of Greb1l in craniofacial development is also evidenced in knockout mice, which develop severe craniofacial abnormalities. In addition, we show that Greb1l-/- zebrafish exhibit a loss of abnormal sensory epithelia innervation. An important role for Greb1l in sensory epithelia innervation development is supported by the eighth cranial nerve deficiencies seen in both affected subjects. In conclusion, we demonstrate that GREB1L is a key player in early inner ear and eighth cranial nerve development. Abnormalities in cochleovestibular anatomy can provide challenges for cochlear implantation. Combining a molecular diagnosis with imaging techniques might aid the development of individually tailored therapeutic interventions in the future.
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Project description:SOX10 (SRY-box 10) mutation may lead to inner ear deformities. However, its molecular mechanisms on inner ear development are not clear. In this work. The inner ear morphology was investigated at different embryonic stages of the SOX10 mutation miniature porcine model with sensorineural hearing loss, and high-throughput RNA-seq and bioinformatics analyses were applied. Our results indicated that the SOX10 mutation in the miniature pigs led to an incomplete partition of the cochlea, a cystic apex caused by fusion from middle and apical turns, cochlear modiolar defects and a shortened cochlear duct. The model demonstrated 173 DEGs and 185 lncRNAs. The down-regulated DEGs most significantly enriched the inflammatory mediator regulation of the TRP channels, arachidonic acid metabolism, and the salivary secretion pathways, while the up-regulated DEGs most significantly enriched the systemic lupus erythematosus and alcoholism pathways. Based on gene cluster analysis, we selected four gene groups: WNT1, KCNQ4, STRC and PAX6.
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Project description:While the cochlea is considered the primary site of the auditory response to bone conduction (BC) stimulation, the paths by which vibratory energy applied to the skull (or other structures) reaches the inner ear are a matter of continued investigation. We present acoustical measurements of sound in the inner ear that separate out the components of BC stimulation that excite the inner ear via ossicular motion (compression of the walls of the ear canal or ossicular inertia) from the components that act directly on the cochlea (cochlear compression or inertia, and extra-cochlear 'third-window' pathways). The results are consistent with our earlier suggestion that the inner-ear mechanisms play a large role in bone-conduction stimulation in the chinchilla at all frequencies. However, the data also suggest the pathways that conduct vibration to the inner ear via ossicular-motion make a significant contribution to the response to BC stimulation in the 1-3 kHz range, such that interruption of these path leads to a 5 dB reduction in total stimulation in that frequency range. The mid-frequency reduction produced by ossicular manipulations is similar to the 'Carhart's notch' phenomenon observed in otology and audiology clinics in cases of human ossicular disorders. We also present data consistent with much of the ossicular-conducted sound in chinchilla depending on occlusion of the ear canal.
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Project description:ObjectiveVestibular impairment has been observed in patients with congenital hearing loss, but little is known about the vestibular anatomy and function of those in this group with inner ear malformations. This study aims to investigate the association between vestibulocochlear anatomy and vestibular function test results in children with inner ear malformations.Study designCase series with chart review.SettingPediatric patients with inner ear malformations presenting with bilateral profound hearing loss at a tertiary hospital from 1999 to 2017.MethodsEars were classified into subgroups based on anatomic abnormalities seen on computed tomography imaging. Cervical vestibular evoked myogenic potential (cVEMP), rotatory chair, and caloric test results were obtained and collated. Descriptive and inferential statistics were calculated.ResultsOf 82 ears, 29.3% had incomplete partition type II malformation, the most common type. The second-most common type was isolated vestibular organ anomaly (20.7%), which is not included in currently accepted categories. Most ears exhibited abnormal vestibular function. Abnormal vestibule volume was associated with a nonreactive cVEMP (P < .001). Radiologically abnormal lateral semicircular canals were associated with abnormal caloric and rotatory chair results (P < .001).ConclusionWith a relatively large number of cases of isolated vestibular organ anomaly not only in our study but also in previous publications, we suggest that this category be added to the subsets of inner ear malformations. Abnormal vestibule volume was significantly associated with a nonreactive cVEMP finding. The majority of patients with hearing loss secondary to inner ear malformations have abnormal vestibular function test results.
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2017-04-24 | PXD003379 | Pride
Project description:SRY-box 10 (SOX10) mutation may lead to inner ear deformities. However, its molecular mechanisms on inner ear development are not clear. In this work, the inner ear morphology was investigated at different embryonic stages of the SOX10 mutation miniature porcine model with sensorineural hearing loss, and high-throughput RNA-seq and bioinformatics analyses were applied. Our results indicated that the SOX10 mutation in the miniature pigs led to an incomplete partition (IP) of the cochlea, a cystic apex caused by fusion from middle and apical turns, cochlear modiolar defects and a shortened cochlear duct. The model demonstrated 173 differentially expressed genes (DEGs) and 185 differentially expressed long non-coding RNAs (lncRNAs). The down-regulated DEGs most significantly enriched the inflammatory mediator regulation of the TRP channels, arachidonic acid metabolism, and the salivary secretion pathways, while the up-regulated DEGs most significantly enriched the systemic lupus erythematosus and alcoholism pathways. Based on gene cluster analysis, we selected four gene groups: WNT1, KCNQ4, STRC and PAX6.
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Project description:BackgroundCongenital auricular deformities (CAD) are prevalent worldwide. The objective of this study is to investigate the effectiveness and safety of ear molding for children with CAD at their early days.MethodsOne hundred and nighty children (under 3 days) with CAD will be included in the study. Participants will be randomly allocated to treatment or waiting list group (n = 95). The treatment group will receive ear molding within 3 days after birth for 2 weeks. The control group will receive usual care and receive the same ear molding at 6th week if spontaneously recover is not occur. Physician and parent assessment of improvement, parent's anxiety, depression, and quality of life and adverse events will be measured at baseline, 3rd and 6th week of initial treatment. The primary outcome recovery rate will be compared between groups using Chi square test. Secondary continuous outcomes will be compared using analysis of variance.DiscussionThis study is the first randomized controlled trial to examine the effectiveness, safety and cost-effectiveness of ear molding for CAD comparing with waiting list, to inform clinical decision of CAD treatments and relevant guideline development.
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Project description:MPSS analysis of signatures from microdissections of mouse inner ear tissues. Keywords: other
2006-10-01 | GSE4965 | GEO
Project description:IntroductionInner ear barotrauma (IEBt) and inner ear decompression sickness (IEDCS) are the two dysbaric inner ear injuries associated with diving. Both conditions manifest as cochleovestibular symptoms, causing difficulties in differential diagnosis and possibly delaying (or leading to inappropriate) treatment.MethodsThis was a systematic review of IEBt and IEDCS cases aiming to define diving and clinical variables that help differentiate these conditions. The search strategy consisted of a preliminary search, followed by a systematic search covering three databases (PubMed, Medline, Scopus). Studies were included when published in English and adequately reporting one or more IEBt or IEDCS patients in diving. Concerns regarding missing and duplicate data were minimised by contacting original authors when necessary.ResultsIn total, 25 studies with IEBt patients (n = 183) and 18 studies with IEDCS patients (n = 397) were included. Variables most useful in differentiating between IEBt and IEDCS were dive type (free diving versus scuba diving), dive gas (compressed air versus mixed gas), dive profile (mean depth 13 versus 43 metres of seawater), symptom onset (when descending versus when ascending or surfacing), distribution of cochleovestibular symptoms (vestibular versus cochlear) and absence or presence of other DCS symptoms. Symptoms of difficult middle ear equalisation or findings consistent with middle ear barotrauma could not be reliably assessed in this context, being insufficiently reported in the IEDCS literature.ConclusionsThere are multiple useful variables to help distinguish IEBt from IEDCS. Symptoms of difficult middle ear equalisation or findings consistent with middle ear barotrauma require further study as means of distinguishing IEBt and IEDCS.
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