Replication of missense OTOG gene variants in a Brazilian cohort of Menière’s Disease

Replication of missense OTOG gene variants in a Brazilian cohort of Menière’s Disease | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Replication of missense OTOG gene variants in a Brazilian cohort of Menière’s Disease View ORCID Profile Giselle Bianco-Bortoletto , View ORCID Profile Geovana Almeida Carneiro , View ORCID Profile Helena Fabbri-Scallet , View ORCID Profile Alberto M. Parra-Perez , View ORCID Profile Karen de Carvalho Lopes , Tatiana de Almeida Lima Sá Vieira , Fernando Freitas Ganança , View ORCID Profile Juan Carlos Amor-Dorado , Andres Soto-Varela , View ORCID Profile Jose A. Lopez-Escamez , View ORCID Profile Edi Lucia Sartorato doi: https://doi.org/10.1101/2025.04.26.25326273 Giselle Bianco-Bortoletto 1 Meniere Disease Neuroscience Research Program, Faculty of Medicine & Health, School of Medical Sciences, The Kolling Institute, University of Sydney , Sydney, New South Wales, Australia 2 Laboratory of Human Molecular Genetics, Center for Molecular Biology and Genetic Engineering-CBMEG, State University of Campinas-UNICAMP , Sao Paulo, Brazil 3 Programa de Pós-Graduação em Ciências Médicas, Faculty of Medical Sciences, State University of Campinas-UNICAMP , Sao Paulo, Brazil Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Giselle Bianco-Bortoletto Geovana Almeida Carneiro 4 Department of Biochemistry and Tissue Biology, Laboratory of Paracrine Signalling in Tissue Organisation-SPOT, Programa de Pós-Graduação em Biologia Molecular e Morfofuncional, Biology Institute, State University of Campinas-UNICAMP , Sao Paulo, Brazil Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Geovana Almeida Carneiro Helena Fabbri-Scallet 2 Laboratory of Human Molecular Genetics, Center for Molecular Biology and Genetic Engineering-CBMEG, State University of Campinas-UNICAMP , Sao Paulo, Brazil 5 Postdoctoral Researcher Program, Faculty of Medical Sciences, State University of Campinas , Sao Paulo, Brazil Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Helena Fabbri-Scallet Alberto M. Parra-Perez 1 Meniere Disease Neuroscience Research Program, Faculty of Medicine & Health, School of Medical Sciences, The Kolling Institute, University of Sydney , Sydney, New South Wales, Australia 6 Otology & Neurotology Group CTS495, Division of Otolaryngology, Department of Surgery, Instituto de Investigación Biosanitaria, ibs.GRANADA, Granada, Universidad de Granada , Granada, Spain 7 Sensorineural Pathology Programme, Centro de Investigación Biomédica en Red en Enfermedades Raras, CIBERER , Madrid, Spain Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Alberto M. Parra-Perez Karen de Carvalho Lopes 8 Otolaryngology and Head and Neck Surgery Department of Federal University of São Paulo , Brazil Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Karen de Carvalho Lopes Tatiana de Almeida Lima Sá Vieira 8 Otolaryngology and Head and Neck Surgery Department of Federal University of São Paulo , Brazil Find this author on Google Scholar Find this author on PubMed Search for this author on this site Fernando Freitas Ganança 8 Otolaryngology and Head and Neck Surgery Department of Federal University of São Paulo , Brazil Find this author on Google Scholar Find this author on PubMed Search for this author on this site Juan Carlos Amor-Dorado 9 Department of Otolaryngology, Hospital Can Misses , Ibiza, Spain Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Juan Carlos Amor-Dorado Andres Soto-Varela 10 Division of Neurotology, Department of Otorhinolaryngology, Complexo Hospitalario Universitario , Santiago de Compostela, Spain 11 Department of Surgery and Medical-Surgical Specialities, Universidade de Santiago de Compostela , Santiago de Compostela, Spain 12 Health Research Institute of Santiago (IDIS) , Santiago de Compostela, Spain Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jose A. Lopez-Escamez 1 Meniere Disease Neuroscience Research Program, Faculty of Medicine & Health, School of Medical Sciences, The Kolling Institute, University of Sydney , Sydney, New South Wales, Australia 6 Otology & Neurotology Group CTS495, Division of Otolaryngology, Department of Surgery, Instituto de Investigación Biosanitaria, ibs.GRANADA, Granada, Universidad de Granada , Granada, Spain 7 Sensorineural Pathology Programme, Centro de Investigación Biomédica en Red en Enfermedades Raras, CIBERER , Madrid, Spain Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jose A. Lopez-Escamez For correspondence: jose.lopezescamez{at}sydney.edu.au sartor{at}unicamp.br Edi Lucia Sartorato 2 Laboratory of Human Molecular Genetics, Center for Molecular Biology and Genetic Engineering-CBMEG, State University of Campinas-UNICAMP , Sao Paulo, Brazil 3 Programa de Pós-Graduação em Ciências Médicas, Faculty of Medical Sciences, State University of Campinas-UNICAMP , Sao Paulo, Brazil Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Edi Lucia Sartorato For correspondence: jose.lopezescamez{at}sydney.edu.au sartor{at}unicamp.br Abstract Full Text Info/History Metrics Supplementary material Data/Code Preview PDF Abstract Ménière’s Disease (MD) is a chronic inner ear disorder defined by recurring episodes of vertigo, fluctuating sensorineural hearing loss, tinnitus, and/or fullness in the ear. Its prevalence varies by region and ethnicity, with scarce epidemiological data in Brazilian population. Although most MD cases are sporadic, Familial MD (FMD) is observed in 5% to 20% of European cases. By exome sequencing, we have found a rare missense variant in the OTOG gene in a Brazilian MD individual with probable European ancestry (chr11:17599671C>T), which was previously reported in a Spanish cohort. Two additional rare missense heterozygous OTOG variants were found in the same proband. Splice Site analysis showed that chr11:17599671C>T may lead to substantial changes generating exonic cis regulatory elements, and protein modelling revealed structural changes in the presence of chr11:17599671C>T, chr11:17576581G>C and chr11:17594108C>T, predicted to highly destabilize protein structure. These findings indicate that missense variants may have an additive effect leading to an unstable Otogelin and support OTOG gene as a key player in the MD pathophysiology. Introduction Ménière’s Disease (MD, MIM 156000) is a rare chronic inner ear disorder, which manifests through recurrent episodes of vertigo, fluctuating sensorineural hearing loss (SNHL), tinnitus, and aural fullness. Its prevalence varies worldwide, ranging from 34 to 190 per 100,000 adults, with familial aggregation and higher occurrence among women and Caucasians ( 1 , 2 ). The lack of epidemiological data in the Brazilian population makes genetic studies an arduous task. Although most MD cases are considered sporadic, Familial Meniere’s Disease (FMD) has been reported in 5% - 20% of cases of European descent ( 3 ). The current diagnostic approach relies on clinical criteria outlined by the Barany Society in 2015 international guidelines, emphasizing clinical stratification and the identification of incomplete phenotypes ( 1 ). Exome and genome sequencing studies combining gene burden tests and segregation analyses support MD as a polygenic condition ( 4 – 6 ). Around 15 genes have been linked to familial MD ( 3 ), including SNHL genes demonstrating autosomal dominant, recessive or digenic inheritance patterns ( 7 , 8 ) supporting genetic heterogeneity. The OTOG gene, encoding Otogelin, an extracellular protein in the tectorial membrane in the organ of Corti ( 9 ) is emerging as a key gene in familial MD ( 10 ). Several missense variants in OTOG have been identified Spanish families with MD, showing aggregation in the coding sequence of constrained regions, that may explain higher MD prevalence in Europeans ( 7 , 10 ). This exome sequencing study aims to identify novel candidate genes in Brazilian patients with MD. Our results replicate a rare missense variant chr11:17599671C>T in the OTOG gene previously reported in a Spanish cohort in a Brazilian MD patient, supporting the role of OTOG in the molecular pathophysiology of MD. Materials and Methods Hearing Profile Audiograms from the worse ear were analysed in R Studio (v.4.4.2) using regression to estimate hearing onset and outcome. Coefficient of determination ( R2 ) and p-values validated the model. Whole Exome Sequencing (WES) WES was performed on DNA from 23 unrelated Brazilian Menière’s disease (MD) patients. Libraries were prepared with Nextera Rapid Exome Enrichment Kit ® (Illumina, Inc., San Diego, CA, USA) and sequenced (2×100 base pairs paired end, ≥100× coverage) on HiSeq™ 2500 (Illumina). Reads were aligned to the GRCh38/hg38 using Burrows-Wheeler Aligner (BWA), variants were called with DeepVariant and filtered for minor allele frequency (MAF) <0.001 (Genome Aggregation Database, gnomAD v4.1.0). The Integrative Genomics Viewer (IGV) assessed read quality. Rare Variant Identification Rare variants were retrieved from previously published sporadic MD (SMD, n=511) ( 10 ) and familial MD (FMD, n=100) ( 4 ) datasets (non-Finnish European MAF 20). Pathogenicity was assessed per American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines ( 11 ). Missense variant density in the OTOG coding sequence was determined using 200 base pair (bp) sliding windows template previously reported ( 10 ), identifying high-density regions (HDR) and low-density regions (LDR), the latter also called constraint coding regions (CCR), per gnomAD v2.1,. Splice Site Prediction Human Splice Finder Pro ( 12 ) predicted donor/acceptor sites, exonic and intronic splicing enhancers (ESE/ISE), exonic and intronic splicing silencers (ESS/ISS), and branch points. Protein Modelling Canonical UniProt sequences were modelled using Modeller ( 13 ) v10.5 through homology-based reconstruction using a template of the WT protein previously reported ( 10 ). Model validation included Discrete Optimized Protein Energy (DOPE), Genetic Algorithm 341 (GA341), and molecular probability density function (molpdf). Additional validation was performed via the Structural Analysis and Verification Server (SAVES v6.1; https://saves.mbi.ucla.edu/ ) for stereochemical quality and atomic interactions ( 14 , 15 ). Structural comparisons were conducted in PyMOL v3.0. DynaMut2 ( 16 ) and MuPro ( 17 ) assessed variant impact on protein stability (ΔΔG). MuPro confidence score (CS) ranged from -1 to 1, with CS0 indicating stabilization. DynaMut2 classified variants as destabilizing for negative predicted free energy change (ΔΔG_pred) values and stabilizing for positive ΔΔG_pred values. Results Clinical Description The study focuses on a male proband who meets definitive MD diagnostic criteria, with a 13-year disease course characterised by recurrent vertigo attacks (25-30 episodes), persistent left-sided tinnitus, fluctuating SNHL, and aural fullness. A comprehensive neurotological evaluation, incorporating video head impulse testing (vHIT) and serial audiometry was conducted, which confirmed bilateral SNHL without vestibular hypofunction. His medical history included well-controlled hypertension and autoimmune disease, with no familial history of auditory or vestibular disorders. Hearing Profile The hearing profile of the Brazilian proband and three Spanish patients carrying the OTOG variant chr11:17599671C>T showed no significant hearing loss progression at any frequency (Supplementary Figure S1; Supplementary Table S1). Rare OTOG variant replicated in Brazilian sample The missense variant chr11:17599671C>T (NFE MAF=0.005) was replicated in both cohorts. Two additional rare OTOG missense variants were identified in the Brazilian proband, chr11:17576581G>C (NFE MAF=0.00001) and chr11:17594108C>T (NFE MAF=0.0004). All were classified as Likely pathogenic per ACMG guidelines ( Table1 ) and located in biologically constraint low-density regions (LDR), suggesting low protein tolerance to variation ( Figure 1 ). View this table: View inline View popup Download powerpoint Table 1. OTOG missense variants found in the proband. Chr11:17599671C>T was replicated in the Spanish cohort. For the three variants together in Otogelin DynaMut2 stability prediction was -1.9kcal/mol, destabilizing the protein. Download figure Open in new tab Figure 1. A . Variant density profile along the OTOG CDS in the NFE, AFR, SAS, EAS, and AMR populations calculated with a 201 bp sliding window. B . Otogelin protein domains (created with IBS software). C . Modelled Otogelin protein showing the three selected variants. D-F . Structural differences between wild type (WT) and mutated Otogelin protein at positions p.850, p.1129 and p.1240. Splice Site Prediction Using HSF Pro, analysis of the three OTOG variants showed significant exonic cis-element alterations for chr11:17599671C>T, including the disruption of five ESEs, as well as the formation of two ESE and seven ESSs (Supplementary Table S2). Protein Modelling In silico analysis revealed that both wild-type and mutated amino acids are in loop regions. Variant chr11:17599671C>T (p.P1240L) was predicted to not form any contacts in the WT structure, however, the mutated amino acid formed a hydrophobic contact with the Proline at p.1236 ( Figure 1D ). For chr11:17594108 C>T (p.P1129L), WT Proline forms several hydrophobic contacts with p.W1144, while the variant Leucine creates new hydrophobic and polar contacts with p.W1144, p.A1520 and p.N1131 ( Figure 1E ). Variant chr11:17576581G>T (p.G850R) replaced Glycine with Arginine at position 850, which is predicted to create three hydrophobic contacts with p.I599 ( Figure 1F ) and altering polar interactions, leading to a short α-helix at p.841-843 (Supplementary Figure S2). Variants chr11:17599671C>T and chr11:17576581G>T were predicted to destabilize the protein in both in silico methods employed, while chr11:17594108 C>T showed conflicting results. When analysed together, mimicking the proband’s protein, DynaMut2 predicted high destabilization values (−1.9kcal/mol) (Supplementary Table S3). Discussion This study replicates a missense variant in a Brazilian patient with SMD previously reported in 2 individuals and 1 family with MD in Spain. There is an overload of missense variants in OTOG gene in FMD ( 10 ). Variant chr11:17599671C>T has been associated with moderate-to-severe flat hearing loss (60 dB) from early onset, involving all frequencies with minor low-frequency variations over time. Interestingly, it has not been reported in non-European individuals. The Brazilian proband, a male with no MD family history and unknown European ancestry, was screened for additional OTOG variants. Two rare heterozygous missense variants chr11:17599671C>T and chr11:17594108 C>T were identified, neither previously associated with disease. The tectorial membrane (TM), an acellular layer above the organ of Corti, plays a key role in sound transmission by enhancing cochlear feedback. Structurally, it consists of collagen, non-glycoproteins, and proteoglycans, with Otogelin, encoded by OTOG , as a key non-collagenous glycoprotein. OTOG knockout mice have revealed its importance in auditory and balance functions, showing phenotypes like detachment of otoconial membranes, structural defects in the TM’s fibrillar network, and reduced TM resistance to sound stimuli ( 18 ). Otogelin stabilizes the TM by interacting with its constituent fibres, and OTOG mutations can cause moderate nonsyndromic SNHL ( 19 ). Protein mutations alter bonding networks, affecting structure and function ( 20 ). Variants chr11:17599671C>T and chr11:17576581G>T are near, and chr11:17594108 C>T is within, the von Willebrand factor D (VWFD) domain in the Otogelin protein, which binds Ca 2+ ions as a reservoir ( 3 ). Rare variations in Otogelin may alter electrostatic interactions and 3D structure ( 7 ). Our study has a limitation, since we could not obtain DNA samples from the proband’s relatives for segregation analysis, but the finding of 3 rare variants in the OTOG gene in the same proband cannot be explained by chance. Conclusion We have found a MD disease patient with 3 rare missense variants in the OTOG gene, which were predicted to destabilize the protein and alter its structure. This is the first time the variant chr11:17599671C>T has been reported in non-Spanish MD patients. These results support OTOG gene as a key player in the MD pathophysiology. Data Availability The OTOG variants chr11:17599671C>T, chr11:17576581G>T and chr11:17594108 C>T have been deposited in ClinVar (SUB15056944. accession number pending). Conflicts of Interest The authors declare no conflicts of interest. Author Contribution Giselle Bianco-Bortoletto: Conceptualization, formal analysis, data curation, investigation, methodology, validation, visualization, writing – original draft. Geovana Almeida Carneiro: Formal analysis, methodology. Helena Fabbri-Scallet: Data curation. Alberto Parra-Perez, Karen de Carvalho Lopes, Tatiana de Almeida Lima Sá Vieira, Fernando Ganança, Juan Carlos Amor-Dorado, Andres Soto-Varela: Resources. Karen de Carvalho Lopes, Tatiana de Almeida Lima Sá Vieira: Writing – original draft. Jose A. Lopez-Escamez, Edi Lucia Sartorato: Conceptualization, funding acquisition, project administration, resources, supervision, validation, writing – review & editing. Funding This work was supported by FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo; grant number 2014/50897-0). GBB was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico-CNPq (grant number 141196/2021-1) and in part by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-CAPES, Brasil (Finance Code 001). JALE has received funds to support research on MD from The University of Sydney (K7013_B3413 Grant), Asociación Sindrome de Meniere España (ASMES) and Meniere’s Society, UK. Ethics Approved by the University of Campinas School of Medical Sciences Ethics Committee (CAAE: 82809524.0.0000.5404); patient consent obtained. Acknowledgments We would like to acknowledge the patient for donating blood to contribute to this study. We thank members of CQMED-UNICAMP for their support. We thank the staff of the Life Sciences Core Facility (LaCTAD) at UNICAMP for the Genomics analysis. References 1. ↵ Lopez-Escamez JA , Carey J , Chung WH , Goebel JA , Magnusson M , Mandalà M , et al. Diagnostic criteria for Menière’s disease . J Vestib Res Equilib Orientat . 2015 ; 25 ( 1 ): 1 – 7 . OpenUrl 2. ↵ Frejo L , Lopez-Escamez JA . Recent advances in understanding molecular bases of Ménière’s disease . Fac Rev . 2023 ; 12 : 11 . OpenUrl PubMed 3. ↵ Parra-Perez AM , Lopez-Escamez JA . Types of Inheritance and Genes Associated with Familial Meniere Disease . J Assoc Res Otolaryngol JARO . abril de 2023 ; 4. ↵ Fisch KM , Rosenthal SB , Mark A , Sasik R , Nasamran CA , Clifford R , et al. The genomic landscape of Ménière’s disease: a path to endolymphatic hydrops . BMC Genomics . junho de 2024 ; 25 ( 1 ): 646 . OpenUrl CrossRef PubMed 5. Gallego-Martinez A , Requena T , Roman-Naranjo P , Lopez-Escamez JA . Excess of Rare Missense Variants in Hearing Loss Genes in Sporadic Meniere Disease . Front Genet . 2019 ; 10 : 76 . OpenUrl CrossRef PubMed 6. ↵ Dai Q , Long L , Zhao H , Wang R , Zheng H , Duan M. Genetic advances in Meniere Disease . Mol Biol Rep [Internet] . mar ço de 2023 [citado 9 de janeiro de 2025 ]; 50 ( 3 ): 2901 – 8 . Disponível em: https://link.springer.com/10.1007/s11033-022-08149-8 OpenUrl 7. ↵ Roman-Naranjo P , Gallego-Martinez A , Soto-Varela A , Aran I , Moleon M del C , Espinosa-Sanchez JM , et al. Burden of Rare Variants in the OTOG Gene in Familial Meniere’s Disease . Ear Hear [Internet] . novembro de 2020 ; 41 ( 6 ): 1598 – 605 . Disponível em: https://journals.lww.com/10.1097/AUD.0000000000000878 http://www.ncbi.nlm.nih.gov/pubmed/33136635 OpenUrl 8. ↵ Roman-Naranjo P , Moleon MDC , Aran I , Escalera-Balsera A , Soto-Varela A , Bächinger D , et al. Rare coding variants involving MYO7A and other genes encoding stereocilia link proteins in familial meniere disease . Hear Res . setembro de 2021 ; 409 : 108329 . OpenUrl CrossRef PubMed 9. ↵ Avan P , Le Gal S , Michel V , Dupont T , Hardelin JP , Petit C , et al. Otogelin, otogelin-like, and stereocilin form links connecting outer hair cell stereocilia to each other and the tectorial membrane . Proc Natl Acad Sci U S A . ezembro de 2019 ; 116 ( 51 ): 25948 – 57 . OpenUrl Abstract / FREE Full Text 10. ↵ Parra-Perez AM , Gallego-Martinez A , Lopez-Escamez JA . An overload of missense variants in the OTOG gene may drive a higher prevalence of familial Meniere disease in the European population . Hum Genet [Internet]. 1° e março de 2024 [citado 10 de janeiro de 2025 ]; 143 ( 3 ): 423 – 35 . Disponível em : doi: 10.1007/s00439-024-02643-8 OpenUrl CrossRef 11. ↵ Oza AM , DiStefano MT , Hemphill SE , Cushman BJ , Grant AR , Siegert RK , et al. Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss . Hum Mutat . novembro de 2018 ; 39 ( 11 ): 1593 – 613 . OpenUrl CrossRef PubMed 12. ↵ Desmet FO , Hamroun D , Lalande M , Collod-Béroud G , Claustres M , Béroud C. Human Splicing Finder: an online bioinformatics tool to predict splicing signals . Nucleic Acids Res [Internet]. 1° e maio de 2009 [citado 10 de janeiro de 2025 ]; 37 ( 9 ): e67 . Disponível em : doi: 10.1093/nar/gkp215 OpenUrl CrossRef PubMed 13. ↵ Šali A , Blundell TL . Comparative Protein Modelling by Satisfaction of Spatial Restraints . J Mol Biol [Internet] . 5 e dezembro de 1993 [citado 10 de janeiro de 2025 ]; 234 ( 3 ): 779 – 815 . Disponível em: https://www.sciencedirect.com/science/article/pii/S0022283683716268 OpenUrl 14. ↵ Laskowski RA , Rullmann JAC , MacArthur MW , Kaptein R , Thornton JM . AQUA and PROCHECK-NMR: Programs for checking the quality of protein structures solved by NMR . J Biomol NMR [Internet] . 1° e dezembro de 1996 [citado 10 de janeiro de 2025 ]; 8 ( 4 ): 477 – 86 . Disponível em : doi: 10.1007/BF00228148 OpenUrl CrossRef PubMed Web of Science 15. ↵ Colovos C , Yeates TO . Verification of protein structures: Patterns of nonbonded atomic interactions . Protein Sci [Internet] . 1993 [citado 21 de abril de 2023 ]; 2 ( 9 ): 1511 – 9 . Disponível em: https://onlinelibrary.wiley.com/doi/abs/10.1002/pro.5560020916 OpenUrl 16. ↵ Rodrigues CHM , Pires DEV , Ascher DB . DynaMut2: Assessing changes in stability and flexibility upon single and multiple point missense mutations . Protein Sci Publ Protein Soc . janeiro de 2021 ; 30 ( 1 ): 60 – 9 . OpenUrl 17. ↵ Cheng J , Randall A , Baldi P. Prediction of protein stability changes for single-site mutations using support vector machines . Proteins. 1° e março de 2006 ; 62 ( 4 ): 1125 – 32 . OpenUrl 18. ↵ Askari M , Moradi Z , Mohammadi M , Lagzian M , Asgharzade S. Prediction and interpretation of rare missense variant in OTOG associated with hearing loss . Genomics [Internet]. 1° e julho de 2021 [citado 10 de janeiro de 2025 ]; 113 ( 4 ): 2793 – 9 . Disponível em: https://www.sciencedirect.com/science/article/pii/S0888754321002299 OpenUrl 19. ↵ Schraders M , Ruiz-Palmero L , Kalay E , Oostrik J , del Castillo FJ , Sezgin O , et al. Mutations of the Gene Encoding Otogelin Are a Cause of Autosomal-Recessive Nonsyndromic Moderate Hearing Impairment . Am J Hum Genet [Internet] . 2 e novembro de 2012 [citado 10 de janeiro de 2025 ]; 91 ( 5 ): 883 – 9 . Disponível em: https://www.sciencedirect.com/science/article/pii/S0002929712005150 OpenUrl 20. ↵ Fang J. A critical review of five machine learning-based algorithms for predicting protein stability changes upon mutation . Brief Bioinform [Internet] . 15 e julho de 2020 [citado 13 de janeiro de 2025 ]; 21 ( 4 ): 1285 – 92 . Disponível em : doi: 10.1093/bib/bbz071 OpenUrl CrossRef View the discussion thread. Back to top Previous Next Posted April 28, 2025. 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